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Neuroprotective and disease-modifying effects of the ketogenic diet

By asmithers | Published January 21, 2016

Maciej Gasior,a Michael A. Rogawski,a and Adam L. Hartmana,b
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Abstract

The ketogenic diet has been in clinical use for over 80 years, primarily for the symptomatic treatment of epilepsy. A recent clinical study has raised the possibility that exposure to the ketogenic diet may confer long-lasting therapeutic benefits for patients with epilepsy. Moreover, there is evidence from uncontrolled clinical trials and studies in animal models that the ketogenic diet can provide symptomatic and disease-modifying activity in a broad range of neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease, and may also be protective in traumatic brain injury and stroke. These observations are supported by studies in animal models and isolated cells that show that ketone bodies, especially β-hydroxybutyrate, confer neuroprotection against diverse types of cellular injury. This review summarizes the experimental, epidemiological and clinical evidence indicating that the ketogenic diet could have beneficial effects in a broad range of brain disorders characterized by the death of neurons. Although the mechanisms are not yet well defined, it is plausible that neuroprotection results from enhanced neuronal energy reserves, which improve the ability of neurons to resist metabolic challenges, and possibly through other actions including antioxidant and anti-inflammatory effects. As the underlying mechanisms become better understood, it will be possible to develop alternative strategies that produce similar or even improved therapeutic effects without the need for exposure to an unpalatable and unhealthy, high-fat diet.

Keywords: Alzheimer’s disease, cellular energetics, epilepsy, ketone bodies, ketogenic diet, mitochondria, neuroprotection, Parkinson’s disease, stroke, traumatic brain injury

Introduction

The ketogenic diet is a high-fat content diet in which carbohydrates are nearly eliminated so that the body has minimal dietary sources of glucose. Fatty acids are thus an obligatory source of cellular energy production by peripheral tissues and also the brain. Consumption of the ketogenic diet is characterized by elevated circulating levels of the ketone bodies acetoacetate, β-hydroxybutyrate and acetone, produced largely by the liver. During high rates of fatty acid oxidation, large amounts of acetyl-CoA are generated. These exceed the capacity of the tricarboxylic acid cycle and lead to the synthesis of the three ketone bodies within liver mitochondria. Plasma levels of ketone bodies rise, with acetoacetate and β-hydroxybutyrate increasing three-fold to four-fold from basal levels of 100 and 200 µmol/l, respectively (Musa-Veloso et al., 2002). In the absence of glucose, the preferred source of energy (particularly of the brain), the ketone bodies are used as fuel in extrahepatic tissues. The ketone bodies are oxidized, releasing acetyl-CoA, which enters the tricarboxylic acid cycle.

The ketogenic diet is an established and effective nonpharmacological treatment for epilepsy (Vining et al., 1998; Stafstrom, 2004; Sinha and Kossoff, 2005). Although the diet is useful in people of all ages, clinical experience suggests that it may be more valuable in children, if only because adults have greater difficulty adhering to it. Importantly, the diet is often effective in pharmacoresistant forms of common epilepsies as well as in the difficult to treat catastrophic epilepsy syndromes of infancy and early childhood such as West Syndrome, Lennox–Gastaut Syndrome, and Dravet Syndrome (Crumrine, 2002; Trevathan, 2002; Caraballoet al., 2005).

Recently, there has been interest in the potential of the ketogenic diet in the treatment of neurological disorders other than epilepsy, including Alzheimer’s disease and Parkinson’s disease. Studies in these neurodegenerative disorders have led to the hypothesis that the ketogenic diet may not only provide symptomatic benefit, but could have beneficial disease-modifying activity applicable to a broad range of brain disorders characterized by the death of neurons. Here, we review evidence from clinical studies and animal models that supports this concept.

Ketogenic diet

The classic ketogenic diet is a high-fat diet developed in the 1920s to mimic the biochemical changes associated with periods of limited food availability (Kossoff, 2004). The diet is composed of 80–90% fat, with carbohydrate and protein constituting the remainder of the intake. The diet provides sufficient protein for growth, but insufficient amounts of carbohydrates for the body’s metabolic needs. Energy is largely derived from the utilization of body fat and by fat delivered in the diet. These fats are converted to the ketone bodies β-hydroxybutyrate, acetoacetate, and acetone, which represent an alternative energy source to glucose. In comparison with glucose, ketone bodies have a higher inherent energy (Pan et al., 2002; Cahill and Veech, 2003). In adults, glucose is the preferred substrate for energy production, particularly by the brain. Ketone bodies are, however, a principal source of energy during early postnatal development (Nehlig, 2004). In addition, ketone bodies, especially acetoacetate, are preferred substrates for the synthesis of neural lipids. Ketone bodies readily cross the blood–brain barrier either by simple diffusion (acetone) or with the aid of monocarboxylic transporters (β-hydroxybutyrate, acetoacetate), whose expression is related to the level of ketosis (Pan et al., 2002; Pierre and Pellerin, 2005).

Today, several types of ketogenic diets are employed for treatment purposes. The most frequently used is the traditional ketogenic diet originally developed by Wilder in 1921, which is based on long-chain fatty acids (Wilder, 1921). In the 1950s, a medium-chain triglyceride diet was introduced, which produces greater ketosis (Huttenlocher et al., 1971). This modification has not been widely accepted because it is associated with bloating and abdominal discomfort and is no more efficacious than the traditional ketogenic diet. A third variation on the diet, known as the Radcliffe Infirmary diet, represents a combination of the traditional and medium-chain triglyceride diets (Schwartz et al., 1989). Its efficacy is also similar to the traditional ketogenic diet.

Although the ketogenic diet was a popular treatment approach for epilepsy in the 1920s and 1930s, its medical use waned after the introduction of phenytoin in 1938. The recognition that the diet may be an effective therapeutic approach in some drug-resistant epilepsies, particularly in children, has led to a resurgence of interest in the last 15 years. The popularization of various low carbohydrate diets for weight loss, such as the Atkins diet (Acheson, 2004), probably also has increased interest in the dietary therapy of epilepsy. In fact, a modified form of the Atkins diet, which is easier to implement than the various forms of the traditional ketogenic diet, may be an effective epilepsy treatment approach (Kossoff et al., 2006).

Clinical studies

Epilepsy

At present, strong evidence exists that the ketogenic diet protects against seizures in children with difficult-to-treat epilepsy (Freeman et al., 1998). Recent reports have raised the possibility that the diet may also improve the long-term outcome in such children (Hemingway et al., 2001; Marsh et al., 2006). In these studies, children with intractable epilepsy who remained on the ketogenic diet for more than 1 year and who experienced a good response to the diet, often had positive outcomes at long-term follow-up 3–6 years after the initiation of diet. Forty-nine percent of the children in this cohort experienced a nearly complete (≥ 90%) resolution in seizures. Surprisingly, even those children who remained on the diet for 6 months or less (most of these children terminated the diet because of an inadequate response) may have obtained a long-term benefit from exposure to the diet. Thirty-two percent of these children had a ≥ 90% decrease in their seizures and 22% became seizure free even without surgery. The diet also allowed a decrease or discontinuation of medications without a relapse in seizures. Of course, in the absence of a control group, it is not possible to be certain that the apparent good response in these children is simply the natural history of the epilepsy in the cohort studied, although these children had, by definition, intractable epilepsy before starting the diet. In any case, the results raise the possibility that the ketogenic diet, in addition to its ability to protect against seizures, may have disease-modifying activity leading to an improved long-term outcome. It is noteworthy that none of the currently marketed antiepileptic drugs has been demonstrated clinically to possess such a disease-modifying effect (Schachter, 2002; Benardo, 2003). Determining whether the ketogenic diet truly alters long-term outcome will require prospective controlled trials.

Alzheimer’s disease

Recent studies have raised the possibility that the ketogenic diet could provide symptomatic benefit and might even be disease modifying in Alzheimer’s disease. Thus, Reger et al. (2004) found that acute administration of medium-chain triglycerides improves memory performance in Alzheimer’s disease patients. Further, the degree of memory improvement was positively correlated with plasma levels of β-hydroxybutyrate produced by oxidation of the medium-chain triglycerides. If β-hydroxybutyrate is responsible for the memory improvement, then the ketogenic diet, which results in elevated β-hydroxybutyrate levels, would also be expected to improve memory function. When a patient is treated for epilepsy with the ketogenic diet, a high carbohydrate meal can rapidly reverse the antiseizure effect of the diet (Huttenlocher, 1976). It is therefore of interest that high carbohydrate intake worsens cognitive performance and behavior in patients with Alzheimer’s disease (Henderson, 2004; Young et al., 2005).

It is also possible that the ketogenic diet could ameliorate Alzheimer’s disease by providing greater amounts of essential fatty acids than normal or high carbohydrate diets (Cunnane et al., 2002; Henderson, 2004). This is because consumption of foods or artificial supplements rich in essential fatty acids may decrease the risk of developing Alzheimer’s disease (Ruitenberg et al., 2001; Barberger-Gateau et al., 2002; Morris et al., 2003a,b).

Parkinson’s disease

One recently published clinical study tested the effects of the ketogenic diet on symptoms of Parkinson’s disease (VanItallie et al., 2005). In this uncontrolled study, Parkinson’s disease patients experienced a mean of 43% reduction in Unified Parkinson’s Disease Rating Scale scores after a 28-day exposure to the ketogenic diet. All participating patients reported moderate to very good improvement in symptoms. Further, as in Alzheimer’s disease, consumption of foods containing increased amounts of essential fatty acids has been associated with a lower risk of developing Parkinson’s disease (de Lau et al., 2005).

Studies in animal models

Epilepsy

Anticonvulsant properties of the ketogenic diet have been documented in acute seizure models in rodents (Appleton and De Vivo, 1973; Huttenlocher, 1976; Hori et al., 1997; Stafstrom, 1999; Likhodii et al., 2000;Thavendiranathan et al., 2000, 2003; Bough et al., 2002). Moreover, there is accumulating evidence from studies in models of chronic epilepsy that the ketogenic diet has antiepileptogenic properties that extend beyond its anticonvulsant efficacy. Thus, in the rat kainic acid model of temporal lobe epilepsy, the development of spontaneous seizures was attenuated by the ketogenic diet and there was a reduction in the severity of the seizures that did occur (Muller-Schwarze et al., 1999; Stafstrom et al., 1999; Su et al., 2000). In addition, animals fed the diet have reduced hippocampal excitability and decreased supragranular mossy fiber sprouting in comparison with rats fed a normal diet. Further evidence supporting the antiepileptogenic activity of the ketogenic diet is the demonstration that the development of spontaneous seizures in inbred EL/Suz mice, a genetic model of idiopathic epilepsy, is retarded by the diet (Todorova et al., 2000). In other studies, caloric restriction, which often occurs with the ketogenic diet, has also been demonstrated to have antiepileptogenic effects in EL/Suz mice (Greene et al., 2001; Mantis et al., 2004). (Although the ketogenic diet is designed to provide calories adequate for growth, patients and animals may eat less because the diet may be unpalatable to some. Thus, the ketogenic diet may be accompanied by an unintentional caloric restriction.)

Alzheimer’s disease

Epidemiological studies have implicated diets rich in saturated fat with the development of Alzheimer’s disease (Kalmijn et al., 1997; Grant, 1999; Morris et al., 2003a, b, 2004; but see Engelhart et al., 2002). Moreover, in transgenic mouse models, high-fat diets increase the deposition of amyloid β (Aβ) peptides (Levin-Allerhand et al., 2002; Shie et al., 2002; George et al., 2004; Ho et al., 2004). These studies, however, did not examine the effects of ketogenic diets rich in fats, when the high lipid content is administered along with severe carbohydrate restriction. Indeed, in a recent series of experiments using a transgenic mouse model of Alzheimer’s disease, a ketogenic diet was found to improve Alzheimer’s pathology. The mice used in this study, which express a human amyloid precursor protein gene containing the London mutation (APP/V717I), exhibit significant levels of soluble Aβ in the brain as early as 3 months of age and show extensive plaque deposition by 12–14 months (Van der Auwera et al., 2005). They also demonstrate early behavioral deficits in an object recognition task. Exposure to a ketogenic diet for 43 days resulted in a 25% reduction in soluble Aβ(1–40) and Aβ(1–42) in brain homogenates, but did not affect performance on the object recognition task. Caloric restriction has also been demonstrated to attenuate β-amyloid depositions in mouse models of Alzheimer disease (Patel et al., 2005; Wang et al., 2005). How the ketogenic diet and caloric restriction affect β-amyloid levels and whether this effect could be disease modifying in Alzheimer’s disease requires further study.

The ketogenic diet could have beneficial effects in Alzheimer’s disease apart from effects on β-amyloid disposition. For example, essential fatty acids in the diet may have beneficial effects on learning, as demonstrated with studies of spatial recognition learning in rodent models of Alzheimer’s disease (Hashimotoet al., 2002, 2005; Lim et al., 2005). Alternatively, the diet might protect against β-amyloid toxicity. Thus, direct application of β-hydroxybutyrate in concentrations produced by the ketogenic diet has been found to protect hippocampal neurons from toxicity induced by Aβ(1–42) (Kashiwaya et al., 2000).

Parkinson’s disease

The most widely used animal model of Parkinson’s disease is based on the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Exposure to MPTP causes degeneration of mesencephalic dopamine neurons, as in the human clinical condition, and is associated with parkinsonian clinical features. The ketogenic diet has not yet been studied in the MPTP or other animal models of Parkinson’s disease. As in epilepsy and Alzheimer’s disease models, however, caloric restriction has been found to have beneficial effects in MPTP models of Parkinson’s disease. This was first demonstrated in rats fed on an alternate-day schedule so that they consume 30–40% less calories than animals with free access to food. The calorie-restricted animals were found to exhibit resistance to MPTP-induced loss of dopamine neurons and less severe motor deficits than animals on the normal diet (Duan and Mattson, 1999). More recently, it has been reported that adult male rhesus monkeys maintained chronically on a calorie-restricted diet are also resistant to MPTP neurotoxicity (Maswood et al., 2004; Holmer et al., 2005). These animals had less depletion of striatal dopamine and dopamine metabolites and substantially improved motor function than did animals receiving a normal diet. In other studies in mice, caloric restriction has been reported to have beneficial effects even when begun after exposure to MPTP (Holmer et al., 2005).

In addition to caloric restriction, several recent reports have indicated that β-hydroxybutyrate may be neuroprotective in the MPTP model. MPTP is converted in vivo to 1-methyl-4-phenylpyridinium (MPP +), which is believed to be the principal neurotoxin through its action on complex 1 of the mitochondrial respiratory chain. In tissue culture, 4 mmol/l β-hydroxybutyrate protected mesencephalic neurons from MPP + toxicity (Kashiwaya et al., 2000). Moreover, subcutaneous infusion by osmotic minipump of β-hydroxybutyrate for 7 days in mice conferred partial protection against MPTP-induced degeneration of dopamine neurons and parkinsonian motor deficits (Tieu et al., 2003). It was proposed that the protective action is mediated by improved oxidative phosphorylation leading to enhanced ATP production. This concept was supported by experiments with the mitochondrial toxin 3-nitropropionic acid (3-NP). 3-NP inhibits oxidative phosphorylation by blocking succinate dehydrogenase, an enzyme of the tricarboxylic acid cycle that transfers electrons to the electron transport chain via its complex II function. The protective effect of β-hydroxybutyrate on MPTP-induced neurodegeneration in mice was eliminated by 3-NP. Moreover, in experiments with purified mitochondria, β-hydroxybutyrate markedly stimulated ATP production and this stimulatory effect was eliminated by 3-NP. Thus, it seems likely that β-hydroxybutyrate is protective in the MPTP model of Parkinson’s disease by virtue of its ability to improve mitochondrial ATP production (Tieuet al., 2003). Whether the ketogenic diet would also be protective in Parkinson’s disease models as a result of increased β-hydroxybutyrate production remains to be determined. It is noteworthy that β-hydroxybutyrate is not anticonvulsant and is unlikely to directly account for the antiseizure activity of the ketogenic diet (Rho et al., 2002). Whether β-hydroxybutyrate contributes in some other way to the beneficial activity of the ketogenic diet in epilepsy therapy remains to be studied.

Ischemia and traumatic brain injury

Much of the neurological dysfunction that occurs in stroke, cerebral ischemia, and acute traumatic brain injury is due to a secondary injury process involving glutamate-mediated excitotoxicity, intracellular calcium overload, mitochondrial dysfunction, and the generation of reactive oxygen species (ROS) (McIntosh et al., 1998). Consequently, the underlying pathophysiological mechanisms may have features in common with those in classical neurodegenerative disorders. Recently, Prins et al. (2005) have reported that the ketogenic diet can confer up to a 58% reduction in cortical contusion volume at 7 days after controlled cortical injury in rats. The beneficial effects of the diet, administered after the injury, only occurred at some postnatal ages despite similar availability of ketone bodies at all ages studied. This led the authors to conclude that differences in the ability of the brain to utilize ketones at different developmental stages may influence the protection conferred (Rafiki et al., 2003; Vannucci and Simpson, 2003; Pierre and Pellerin, 2005). In a previous study, a 48-h fast, which results in similar short-term ketosis as that achieved by the ketogenic diet, was found to protect rats against neuronal loss in the striatum, neocortex, and hippocampus produced by 30-min four-vessel occlusion (Marie et al., 1990). There was also a reduction in mortality and the incidence of postischemic seizures in fasted animals. Thus, there is evidence that the ketogenic diet has neuroprotective activity in both traumatic and ischemic brain injury. An additional study found that rats receiving a ketogenic diet are also resistant to cortical neuron loss occurring in the setting of insulin-induced hypoglycemia (Yamada et al., 2005).

Although the mechanism whereby the ketogenic diet confers protection in these diverse injury models is not well understood, β-hydroxybutyrate could play a role. The ketone body would presumably serve as an alternative energy source to mitigate injury-induced ATP depletion. In fact, exogenous administration of β-hydroxybutyrate can reduce brain damage and improve neuronal function in models of brain hypoxia, anoxia, and ischemia (Cherian et al., 1994; Dardzinski et al., 2000; Suzuki et al., 2001, 2002; Smith et al., 2005). In addition, the other ketone bodies, acetoacetate and acetone, which are β-hydroxybutyrate metabolites and can also serve as alternative energy sources, have similar neuroprotective effects (Garcia and Massieu, 2001; Massieu et al., 2001, 2003; Noh et al., 2006). Interestingly, in rats receiving a ketogenic diet, neuronal uptake of β-hydroxybutyrate is increased after cortical impact injury in comparison with animals receiving a standard diet (Prins et al., 2004). Thus, the ketogenic diet may promote delivery of β-hydroxybutyrate to the brain.

Cellular mechanisms underlying the neuroprotective activity of the ketogenic diet

Effects on energy metabolism

As noted above, ketone bodies, including β-hydroxybutyrate, that are produced during consumption of the ketogenic diet may serve as an alternative source of energy in states of metabolic stress, thus contributing to the neuroprotective activity of the diet. In fact, β-hydroxybutyrate may provide a more efficient source of energy for brain per unit oxygen than glucose (Veech et al., 2001). Recently, using microarrays to define patterns of gene expression, Bough et al. (2006) made the remarkable discovery that the ketogenic diet causes a coordinated upregulation of hippocampal genes encoding energy metabolism and mitochondrial enzymes. Electron micrographs from the dentate/hilar region of the hippocampus showed a 46% increase in mitochondrial profiles in rats fed the ketogenic diet. Thus, the ketogenic diet appears to stimulate mitochondrial biogenesis. Moreover, there was a greater phosphocreatine : creatine ratio in the hippocampal tissue, indicating an increase in cellular energy reserves, as expected from the greater abundance of mitochondria. In sum, during consumption of the ketogenic diet, two factors may contribute to the ability of neurons to resist metabolic stress: a larger mitochondrial load and a more energy-efficient fuel. In combination, these factors may account for the enhanced ability of neurons to withstand metabolic challenges of a degree that would ordinarily exhaust the resilience of the neurons and result in cellular demise.

Effects on glutamate-mediated toxicity

Interference with glutamate-mediated toxicity, a major mechanism underlying neuronal injury, is an alternative way in which the ketogenic diet could confer neuroprotection, although the available evidence supporting this concept is scant. Thus, acetoacetate has been shown to protect against glutamate-mediated toxicity in both primary hippocampal neuron cell cultures; however, a similar effect occurred in an immortalized hippocampal cell line (HT22) lacking ionotropic glutamate receptors (Noh et al., 2006). Acetoacetate also decreased the formation of early cellular markers of glutamate-induced apoptosis and necrosis, probably through the attenuation of glutamate-induced formation of ROS, as discussed below.

Effects on γ-aminobutyric acid systems

Another possible way in which the ketogenic diet may confer neuroprotection is through enhancement of γ-aminobutyric acid (GABA) levels, with a consequent increase in GABA-mediated inhibition (Yudkoff et al., 2001). Thus, ketone bodies have been demonstrated to increase the GABA content in rat brain synaptosomes (Erecinska et al., 1996), and, using in-vivo proton two-dimensional double-quantum spin-echo spectroscopy, the ketogenic diet was associated with elevated levels of GABA in some but not all human subjects studied (Wang et al., 2003). Rats fed a ketogenic diet did not, however, show increases in cerebral GABA (al-Mudallal et al., 1996).

Antioxidant mechanisms

Enhancement of antioxidant mechanisms represents an additional potential mechanism of neuroprotection. For example, ketone bodies have been shown to reduce the amount of coenzyme Q semiquinone, thereby decreasing free radical production (Veech, 2004).

A key enzyme in the control of ROS formation is glutathione peroxidase, a peroxidase found in erythrocytes that prevents lipid peroxidation by reducing lipid hydroperoxides to their corresponding alcohols and reducing free hydrogen peroxide to water. The ketogenic diet induces glutathione peroxidase activity in the rat hippocampus (Ziegler et al., 2003).

The ketogenic diet also increases production of specific mitochondrial uncoupling proteins (UCPs) (Sullivanet al., 2004). For example, in mice fed a ketogenic diet, UCP2, UCP4, and UCP5 were increased, particularly in the dentate gyrus. UCPs serve to dissipate the mitochondrial membrane potential, which, in turn, decreases the formation of ROS. Thus, juvenile mice fed a ketogenic diet had higher maximum mitochondrial respiration rates than those fed a control diet. Oligomycin-induced ROS production was also lower in the ketogenic diet-fed group. The ketogenic diet likely induces UCP production via fatty acids (Freeman et al., 2006). Levels of many polyunsaturated fatty acids are elevated in human patients on the ketogenic diet (Fraser et al., 2003). In fact, in patients with epilepsy, levels of one polyunsaturated fatty acid, arachidonate, were found to correlate with seizure control, although it has not yet been shown that arachidonate induces UCP production.

Effects on programmed cell death

The ketogenic diet may also protect against various forms of cell death. For example, the diet was protective against apoptotic cell death in mice induced by the glutamate receptor agonist and excitotoxin kainate, as evidenced by reductions of markers of apoptosis, including terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling and caspase-3 staining, in neurons in the CA1 and CA3 regions of the hippocampus (Noh et al., 2003). Activation of caspase-3, a member of a larger family of cysteine proteases, has been implicated in neuronal cell death produced by different brain insults including seizures and ischemia (Gillardon et al., 1997; Chen et al., 1998). Apoptosis in seizure models can proceed via a number of molecular pathways (McIntosh et al., 1998; Fujikawa, 2005). One molecule that may play a role is calbindin, which is increased in mice on the ketogenic diet (McIntosh et al., 1998; Noh et al., 2005a). Calbindin is believed to have neuroprotective activity through its capacity to buffer intracellular calcium, which is a mediator of cell death (Mattson et al., 1995; Bellido et al., 2000). Further, protection by the ketogenic diet may be mediated by the prevention of kainic acid-induced accumulation of the protein clusterin (Noh et al., 2005b), which can act as a prodeath signal (Jones and Jomary, 2002).

Anti-inflammatory effects

It is well recognized that inflammatory mechanisms play a role in the pathophysiology of acute and chronic neurodegenerative disorders (Neuroinflammation Working Group, 2000; Pratico and Trojanowski, 2000;Chamorro and Hallenbeck, 2006). Inflammation has also been hypothesized to contribute to the development of chronic epilepsy (Vezzani and Granata, 2005). It is therefore of interest that fasting (a state associated with ketonemia, as in the ketogenic diet) or a high-fat diet has been associated with effects on inflammatory mechanisms (Palmblad et al., 1991; Stamp et al., 2005). A link between the ketogenic diet, anti-inflammatory mechanisms, and disease modification of neurological disease is still highly tentative. It is, however, noteworthy that intermittently fasted rats have increased expression of the cytokine interferon-γ in the hippocampus, and it was further shown that the cytokine conferred protection against excitotoxic cell death (Lee et al., 2006). The high fatty acid load of the ketogenic diet may also activate anti-inflammatory mechanisms. For example, it has been shown that fatty acids activate peroxisome proliferator-activated receptor α, which may, in turn, have inhibitory effects on the proinflammatory transcription factors nuclear factor-κB and activation protein-1 (Cullingford, 2004).

Carbohydrate restriction as a protective mechanism

A key aspect of the ketogenic diet is carbohydrate restriction. The role of decreased carbohydrates in neuroprotection has been investigated through the use of 2-deoxy-d-glucose (2-DG), a glucose analog that is not metabolized by glycolysis. Lee et al. (1999) found that administration of 2-DG to adult rats at a nontoxic dose (200 mg/kg) for 7 consecutive days produced dramatic protection against hippocampal damage and functional neurological deficits induced by the seizure-inducing excitotoxin kainate. In addition, 2-DG was protective against glutamate-induced and oxidative stress-induced neuronal death in cell culture. The authors also found that reduced glucose availability induces stress proteins, including GRP78 and HSP70, which they proposed act to suppress ROS production, stabilize intracellular calcium, and maintain mitochondrial function.

Conclusions

A wide variety of evidence suggests that the ketogenic diet could have beneficial disease-modifying effects in epilepsy and also in a broad range of neurological disorders characterized by death of neurons. Although the mechanism by which the diet confers neuroprotection is not fully understood, effects on cellular energetics are likely to play a key role. It has long been recognized that the ketogenic diet is associated with increased circulating levels of ketone bodies, which represent a more efficient fuel in the brain, and there may also be increased numbers of brain mitochondria. It is plausible that the enhanced energy production capacity resulting from these effects would confer neurons with greater ability to resist metabolic challenges. Additionally, biochemical changes induced by the diet – including the ketosis, high serum fat levels, and low serum glucose levels – could contribute to protection against neuronal death by apoptosis and necrosis through a multitude of additional mechanisms, including antioxidant and antiinflammatory actions. Theoretically, the ketogenic diet might have greater efficacy in children than in adults, inasmuch as younger brains have greater capacity to transport and utilize ketone bodies as an energy source (Rafiki et al., 2003;Vannucci and Simpson, 2003; Pierre and Pellerin, 2005).

Controlled clinical trials are required to confirm the utility of the diet as a disease-modifying approach in any of the conditions in which it has been proposed to be effective. A greater understanding of the underlying mechanisms, however, should allow the diet to be more appropriately studied. Indeed, there are many as yet unanswered questions about the use of the diet. For example, in epilepsy, how long an exposure to the diet is necessary? Do short periods of exposure to the diet confer long-term benefit? Why can the protective effects of the diet be readily reversed by exposure to carbohydrates in some but not all patients? In situations of acute neuronal injury, can the diet be administered after the neuronal injury, and if so, what time window is available? Does monitoring the diet through measurements of biochemical parameters improve efficacy and, if so, what is the best marker to monitor? Finally, the most fundamental research questions are what role ketosis plays, if any, in the therapeutic effects of the diet, and whether low glucose levels contribute to or are necessary for its symptomatic or proposed disease-modifying activity.

Moreover, a better understanding of the mechanisms may provide insights into ketogenic diet-inspired therapeutic approaches that eliminate the need for strict adherence to the diet, which is unpalatable, difficult to maintain, and is associated with side effects such as hyperuricemia and nephrolithiasis, and adverse effects on bone health and the liver (Freeman et al., 2006). A variety of approaches have been devised that allow ketosis to be obtained without the need to consume a high fat, low carbohydrate diet. The simplest is the direct administration of ketone bodies, such as through the use of the sodium salt form of β-hydroxybutyrate. Toxicological studies in animals have demonstrated that β-hydroxybutyrate sodium is well tolerated, and that theoretical risks such as acidosis and sodium and osmotic overload can be avoided by careful monitoring of blood parameters (Smith et al., 2005). Intravenous β-hydroxybutyrate has the potential to provide neuroprotection against ischemia during some surgical procedures, such as cardiopulmonary bypass. Owing to its short half-life, β-hydroxybutyrate sodium is, however, not suitable for long-term therapy in the treatment of chronic neurodegenerative disorders. In these circumstances, orally bioavailable polymers of β-hydroxybutyrate and its derivatives with improved pharmacokinetic properties may be of utility (Veech, 2004; Smith et al., 2005). Another interesting alternative to the ketogenic diet is the administration of metabolic precursors of ketone bodies. Among potential precursor molecules, 1,3-butanediol and 1,3-butanediol acetoacetate esters have been most extensively studied. These compounds are metabolized in a chain of enzymatic reactions in the plasma and liver to the same ketone bodies that are produced during the ketogenic diet (Desrochers et al., 1992, 1995; Ciraolo et al., 1995). Although each of the aforementioned alternatives is still early in development, the idea of developing the ketogenic diet in a ‘pill’ is very attractive and may be approachable.

Acknowledgements

We thank Amy French and Jessica Yankura for their helpful comments.

Sponsorship: This work was supported by the Intramural Research Program of the NINDS, NIH.

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Nigella Sativa Concoction Induced Sustained Seroreversion in HIV Patient

By asmithers | Published January 14, 2016

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Afr J Tradit Complement Altern Med. 2013; 10(5): 332–335.
Published online 2013 Aug 12.
Abdulfatah Adekunle Onifade,corresponding author1 Andrew Paul Jewell,2 and Waheed Adeola Adedeji3
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Abstract

Nigella sativa had been documented to possess many therapeutic functions in medicine but the least expected is sero-reversion in HIV infection which is very rare despite extensive therapy with highly active anti-retroviral therapy (HAART). This case presentation is to highlight the complete recovery and sero-reversion of adult HIV patient after treatment with Nigella sativa concoction for the period of six months. The patient presented to the herbal therapist with history of chronic fever, diarrhoea, weight loss and multiple papular pruritic lesions of 3 months duration. Examination revealed moderate weight loss, and the laboratory tests of ELISA (Genscreen) and western blot (new blot 1 & 2) confirmed sero-positivity to HIV infection with pre-treatment viral (HIV-RNA) load and CD4 count of 27,000 copies/ml and CD4 count of 250 cells/ mm3respectively. The patient was commenced on Nigella sativa concoction 10mls twice daily for 6 months.. He was contacted daily to monitor side-effects and drug efficacy. Fever, diarrhoea and multiple pruritic lesions disappeared on 5th, 7th and 20th day respectively on Nigella sativa therapy. The CD4 count decreased to 160 cells/ mm3 despite significant reduction in viral load (≤1000 copies/ml) on 30th day on N. sativa. Repeated EIA and Western blot tests on 187th day on Nigella sativa therapy was sero-negative. The post therapy CD4 count was 650cells/ mm3 with undetectable viral (HIV-RNA) load. Several repeats of the HIV tests remained sero-negative, aviraemia and normal CD4 count since 24 months without herbal therapy. This case report reflects the fact that there are possible therapeutic agents in Nigella sativa that may effectively control HIV infection.

Keywords: Nigella sativa, sero-reversion, HIV infection

Introduction

HIV infection was regarded by scientists as the worst epidemic in recent decades and almost 2/3rd of the 33.3 million infected people live in Africa (UNAIDS, 2010). No infectious disease or organism claimed 1.8 million of both adult and children lives in a year (2009) except HIV/AIDS. Despite efforts on availability of free treatment of the infection, only 5.2 million of 22.5 million people living with HIV/AIDS in Africa could access free antiretroviral therapy in 2009 (UNAIDS, 2010). All the attempts to cure the HIV infection proved abortive although progress had been made on controlling almost all the steps involved in the viral replication cycle (Kindt et al, 2007).

Introduction of highly active antiretroviral therapy (HAART) had effectively reduced the death associated with HIV infection. Although many of the HIV patients on HAART recover from HIV/AIDS infection and become aviraemia within 100 days of commencement of therapy but sero-reversion is very rare (Abbas et al, 2000; Finzi & Siliciano, 1998 and Kindt et al, 2007). Few cases of sero-reversion in HIV patients occurred at early stage of HIV infection or in children of HIV infected mothers (Coyne et al, 2007; Jurriaans et al, 2004and Kassutto et al, 2005). The general dogma of un-curability of HIV infection had been challenged by recent spontaneous and drug induced complete recovery with sero-reversion (Onifade et al, 2012). Even herbal therapy had been associated with sero-reversion and full recovery from HIV/AIDS (Lu et al, 1997and Onifade et al, 2012).

Herbal remedy is a substance that contains active ingredients which are parts of plants or plant materials, or combinations used to treat a multitude of ailments throughout the world (WHO, 2002). Many herbal remedies had played many roles in treatment of HIV/AIDS ranging from opportunistic infections to the inhibition of the viral replication (Cos et al, 2008 and Kong et al, 2003). Tat (p14 regulatory protein that activates proviral DNA transcription) had been documented to be inhibited by pentosan poly-sulphate, a carbohydrate derivative (Watson et al, 1999). Reverse transcription and HIV induced cell fusion is also inhibited by Ancistrocladus korupensis, a liana (Matthee et al, 1999). A canolide (coumarin) from tropical forest tree (Calophyllum lanigerum) was documented to possess non-nucleoside reverse transcriptase inhibitory potential in potency (Dhamaratne, et al 2002). Some Chinese medicines have been reported to cause sero-reversion in HIV patients (Lu et al 1997).

Nigella sativa is a popular herb that have been in use in many forms (root, leaf and seed) since many centuries as dated in Islamic and Christian history (Al-Bukhari, 1976 and Isaiah). It is widely available in Asia and Mediterranean regions. Many research studies have been documented on the attributed role ofNigella sativa in treatment of various ailments ranging from infectious to non-infectious diseases (Rhandhawa, 2008). N. sativa was documented to increase T helper cell and other leucocytes (Bamosa et al, 1997 and El-Kadi & Kandil, 1986). The accelerating wound healing effect of N. sativa had been established in rats and humans (Ahmed et al, 1995). It has potent anti-inflammatory, pyrexic and analgesic effects (Al-Ghamdi, 2001 and Houghton et al, 1995). It has been demonstrated to be useful in ameliorating allergic diseases (Badar, 1960). Nigella sativa was documented to be potent antimicrobial agent on bacteria, fungi, protozoa and viruses (Topozada et al, 1965; Alijabre et al, 2005 and Akhtar & Riffat, 1991). However, its antiretroviral (HIV) efficacy had not been well documented, thus propelling the reporting of this presentation.

Case Presentation

YB (25/Os), a 46 year old man, was an artisan (panel beater) who was recruited via the herbalist into the prospective (doctoral) research study and presented with fever, diarrhoea, weight loss and malaise of 3 months duration. He had multiple popular pruritic skin lesions and weight loss evidenced by prominent zygomatic process with sero-positivity to HIV tests (ELISA and confirmed by Western blot). The pre-treatment CD4 count and viral (HIV-RNA) load were 250cells/mm3 and 27, 000 copies/ml respectively. Herbal therapist commenced treatment by dispensing 10mls three times daily of Nigella sativa concoction for 4 months effective from August 2009. He was monitored daily and visited regularly to ascertain the effectiveness of the herbal concoction. However, because of the patient’s occupation schedule (worked 7am – 7pm daily), he could only take the medication twice daily, thus lasting for almost 6 months (January 2010). The fever, malaise and diarrhoea disappeared on the 5th and 7th day respectively. The multiple papular pruritic lesions disappeared on the 20th day. However, the 1st monthly CD4 count was reduced drastically (160 cells/ mm3) despite rapid clinical improvement and significant viral (HIV-RNA) load (1000 copies/ml). Surprisingly, the CD4 count increased gradually from the 2nd month and viral load became undetectable. The CD4 count and viral (HIV-RNA) repeated at the end of therapy were 650cells/ mm3 and undetectable (≤ 50copies/ml) respectively. HIV screening (EIA) and Western blot were repeated on 187th day on herbal concoction therapy and were both negative. The patient was followed up regularly with repeated HIV screening, confirmation (Western blot), CD4 count and viral (HIV-RNA), with all showing sero-negativity and undetectable viral load with normal CD4 count (≥750cells/ mm3). The patient was not on HAART before, during or after the Nigella sativa concoction therapy.

Comments

The un-scientific claims by herbal therapists on diseases led to the research study to determine the effectiveness of herbal remedies in HIV infection. Although HIV infection and un-expected treatment outcome (sero-reversion) had generated controversy, investigational research and reporting could help in the confirmation or rejection of documented claims in many parts of the world. There are many documented roles of herbal remedies in treatment of diseases but sustained sero-reversion and complete recovery was the least expected in HIV infection. Sero-reversion and complete recovery of HIV patient taking Nigella sativahad not been reported despite many pharmacologic and therapeutic functions associated with the herbal products from this plant (Al-Ghamdi, 2001; Aljabre et al, 2005; Bamosa et al, 1997; Houghton et al, 1995;Morsi, 2000; Randhawa, 2008).

The initial decline in CD4 count despite significant clinical improvements by N. sativa concoction is an indication that CD4 count is not enough to monitor the effectiveness of herbal therapy in HIV infection. Likewise 3-month CD4 count is not adequate to determine efficacy of therapy in HIV infection. This is confirmed by significant decrease in viral (HIV-RNA) load with disappearance of signs and symptoms associated with HIV infection in this patient. This is in contrary to the general knowledge that effective antiretroviral therapy (HAART) increases the CD4 count and reduces viral load significantly within 100 days of commencement with therapy. This patient’s case despite poor adherence to medication (twice daily medication instead of thrice as prescribed by herbal therapist) is in support of earlier findings that herbal remedies are not only effective in HIV infection but caused sustained sero-reversion (Lu et al, 1997 andOnifade et al, 2012).

HIV patients on HAART normally experience rapid decrease in viral load with increase in CD4 count due to inhibition of steps in viral replication. Thus, HAART is virustatic. Nigella sativa concoction is likely to be virucidal because viral load reduced significantly and symptoms and signs associated with HIV infection disappeared despite reduction in CD4 count at early phase of treatment in this patient. This is in support of earlier studies that Nigella sativa and protease inhibitor (Ro 31-8959) selectively lyse viral infected cells (Levin et al, 2010 and Rhandawa, 2008). The likely virucidal effect of Nigella sativa therapy on HIV infected cells might explain the initial decrease in CD4 count due to excess CD4 T cell lysis when compared to lymphoiesis. This is confirmed by significant viral load reduction to undetectable level within 3 months commensurable with HAART.

The sustained sero-reversion caused by Nigella sativa might be due to complete absence of HIV infected cells from the body like ‘Berlin’ patient (Hutter et al 2009). Because the half-life of circulating IgM and IgG are 5 and 23 days respectively, absence of the virus (antigen) would halt further B or plasma cell secretion. Because productive short half-life (24 hours) CD4 T cells produce 93–97% of plasma virus, their rapid lysis or viral replication inhibition would cause viral load reduction to undetectable level on antiretroviral therapy. However, HIV from productively infected long lived macrophage (14 days), resting or memory CD4 T cells (about 50 years) that account for 1-7% plasma HIV, continue to evoke antibody production (Finzi and Siliciano, 1998).

It was concluded that the sustained sero-reversion induced by Nigella sativa concoction in this HIV patient means that all HIV cells at all stages in infected cells in the body must have been lysed. Therefore, there is need to further study more HIV patients on Nigella sativa therapy and its virucidal effect on this pandemic virus.

Declaration

We declare that there is no conflict of interest in this publication.

​

Table 1

Monthly CD4 count, viral load and HIV tests of the patient

Acknowledgement

We appreciated the support given by the ex-HIV patient (25 Os) for this case report to be made public. Herbal therapist declared that Nigella sativa concoction contained 60% N.sativa seed and 40% honey

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Anti-inflammatory and Antimicrobial Effects of Heat-Clearing Chinese Herbs: A Current Review

By asmithers | Published January 7, 2016

Tradit Complement Med

 

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Abstract

Inflammation is a normal immune response; but if the body’s regulation of inflammation is dysfunctional, then it will have an adverse effect on the body. Although use of modern drugs for inflammation has a relieving effect, it is still unsatisfactory. Moreover, the emergence of drug-resistant strains and even new kinds of microorganisms is causing significant morbidity and mortality. Recently, more attention has been focused on herbal medicine to treat various diseases because of the ability of the herbs to affect multiple target signaling pathways and their multiple mechanisms of action. Thus, a large number of studies have reported on the anti-inflammatory and antimicrobial effects of the traditional Chinese herbs. Literature survey was performed by conducting systematic electronic search in PubMed, Science Direct, Google Scholar, and in books. This review has listed 11 heat-clearing Chinese herbs (HCCHs) including Scutellaria baicalensis (黃芩 Huáng Qín), Coptis chinensis (黃連 Huáng Lián), Flos Lonicerae (金銀花 Jīn Yín Hūa), Forsythia suspensa (連翹 Lián Qiào), Isatidis Folium (大青葉 Dà Qīn Yè), Radix Isatidis (板藍根 Bǎn Lán Gēn), Viola yedoensis (紫花地丁 Zǐ Huā Dì Dīn), Pulsatilla Radix (白頭翁 Bái Tóu Wēn), Andrographis paniculata (穿心蓮 Chuān Xīn Lián), Houttuynia cordata (魚腥草 Yú Xīng Cǎo), and Patrinia Herba (敗醬草 Bài Jiàn Cǎo), which have anti-inflammatory and antimicrobial effects, and has described their effects through different mechanisms of action and multiple targets. Their ability to affect multiple target signaling pathways and their potential mechanisms of action contributing to their anti-inflammatory and antimicrobial activity may be related to their action of removing heat and counteracting toxicity. Further studies are needed on the collection of HCCHs to know the detailed mechanism of action of herbs in this group for the assessment of effective drug.

Keywords: Anti-inflammatory activity, Antimicrobial activity, Heat-clearing Chinese herbs, Traditional Chinese Medicine

INTRODUCTION

Inflammation is a part of the immune response that can prevent infection through production of pro-inflammatory cytokines and generation of inflammatory mediators in response to microbial products.[1] Although inflammation is crucial to maintaining the health and integrity of an organism, when the inflammatory process is poorly controlled, it can cause massive tissue destruction and a series of chain reactions.[2,3,4] The current treatment of inflammatory disorders involves extensive use of nonsteroidal anti-inflammatory drugs and corticosteroids. Although use of modern drugs for inflammation has a relieving effect, it is still unsatisfactory.[5] Moreover, bacterial resistance to antibiotics and the emergence of new kinds of microorganisms are becoming an increasing problem all over the world, causing significant morbidity and mortality.[6,7] In order to combat this problem, novel antibiotic and anti-inflammatory compounds need to be found which are both effective and safe.

Traditional Chinese Medicine (TCM) has been used in China over thousands of years for the prevention and treatment of various diseases.[6,8,9] TCM uses yin–yang theory to explain the organizational structure, physiological functions, and pathological changes in the human body and to guide diagnosis and treatment of disease.[5,10] Although yin and yang are contradictory in nature, they depend on each other for existence. Keeping balance between yin and yang is very important to maintain the healthy state of human body. TCM theory states that the occurrence of the disease depends on the interaction between zheng qi (nonpathogenic qi) and xie qi (pathogenic qi). The idea of disease is the struggle between pathogenic qi and nonpathogenic qi; in this struggle process, there will be changes between yin and yang. TCM holds that variation between the evil aspect and healthy trend determines the occurrence of disease. Therefore, in TCM, inflammatory and antimicrobial therapy lies in strengthening the healthy trend and dispelling the evil aspect in order to keep a balanced state between yin and yang.[5,11]

Herbal medicine is one of the main components of TCM which has long been used for its multiple types of disease treatment. In recent times, it is making a rapid progress in scientific investigation and attracting great attention due to the good therapeutic effects and minimal side effects of the herbs.[6,8,12] Chinese herbs used in the treatment of diseases are grouped into many categories. One of these is heat-clearing Chinese herbs (HCCHs). Herbs in this group are mostly cold in nature and can clear away heat, purge fire, dry dampness, cool blood, and relieve toxic material. Their main action is clearing away interior heat, and thus they are considered to be antipyretic.[11,13] Because of all these properties, HCCHs may be effective in the treatment of inflammatory disease and microbial infection. This review tries to summarize the effect of HCCHs which have shown anti-inflammatory and antimicrobial activities and their mechanisms of action.

Scutellaria baicalensis (黃芩 Huáng Qín)

Scutellaria baicalensis is a species of flowering plant belonging to Lamiaceae family It is a heat-clearing, phlegm-removing herb, traditionally used to cool heat, drain fire, clear damp-heat, stop bleeding, calm the fetus, and descend yang.[11,13,14] The dry root part of Sc. baicalensis has many pharmacological effects including antipyretic, hepatoprotective, antihypertensive, diuretic, and antibiotic activities. It is mildly sedating and also used to treat dysentery and chronic hepatitis.[6,7,14,15]Sc. baicalensis has distinct effects in the treatment of inflammatory diseases; it alleviates inflammation by decreasing the expression of interleukin (IL)-1b, IL-6, and IL-12, and the production of tumor necrosis factor (TNF)-α and soluble intercellular adhesion molecule-1 (ICAM-1).[5,16] In Xie xin herbal decoction, huang qin, in combination with huang lian, inhibits nitric oxide (NO) production in vitro and in vivo in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Oroxylin A, which is a flavonoid found in dried root of Sc. baicalensis, has also shown good anti-inflammatory effect.[17,18] Moreover, Sc. baicalensis has antibacterial effect against Helicobacter pylori as well as inhibits the growth of Escherichia coli B, coagulase-negative staphylococci, and Saccharomyces cerevisiae.[7,15]

Coptis chinensis (黃連 Huáng Lián)

Coptis chinensis belongs to Ranunculaceae family. Traditionally, it has been used to drain fire, detoxify and disinfect, stop bleeding, cure eczema, burns, and ulcer, and to descend yang.[7,11,13,14,19] The main pharmacodynamic properties have long been recognized in the treatment of intestinal infections including acute gastroenteritis, cholera, and bacillary dysentery. It also used for treating various diseases including skin diseases, conjunctivitis, otitis, and hypertension.[14,19,20]C. chinensis has been demonstrated to have anti-inflammatory effects through different mechanisms. It inhibits TNF-induced Nuclear factor-kappaB (NF-kB) signaling in human keratinocytes by blocking the NF-kB–dependent pathway. It also decreases Th17 cytokine secretion and differentiation by activation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and down-regulation of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and retinoic acid-related orphan receptor ϒt (RORγt) expression. It also reduces Th1 cytokine secretion and differentiation by inhibition of protein 38 (p38) mitogen activated protein kinase (MAPK) and Jun N-terminal kinase (JNK) activation along with down-regulation of STAT1 and STAT4 activities.[21,22] In combination with other herbs, C. chinensis exhibited a good anti-inflammatory effect; the ethanol extract from Zuojin Pill inhibited inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), IL-6, IL-1β, and TNF-α expression by preventing the nuclear translocation of the NF-κB p50 and p65 subunits in RAW 264.7 cells.[23] Another Chinese medicinal formula, IBS-20, containing C. chinensis decreased LPS-stimulated pro-inflammatory cytokine secretion from JAWS II dendritic cells and also blocked the interferon gamma (IFNγ)-induced drop in transepithelial electric resistance which is an index of permeability, in fully differentiated Caco-2 monolayer.[24]C. chinensis has also significant antimicrobial activity against a variety of microorganisms including bacteria, viruses, fungi, protozoans, helminths, and Chlamydia, including Staphylococcus aureus, Pseudomonas aeruginosa, E. coli, Propionibacterium acnes, Streptococcus pneumoniae, Vibrio cholerae, Bacillus anthracis, Bacillus dysenteriae, and Sa. cerevisiae.[7,21,25] Berberine, the major active component of C. chinensis, was found to be bactericidal on V. cholera and capable of inhibiting bacterial adherence to mucosal or epithelial surfaces.[26]

Flos Lonicerae (金銀花 Jīn Yín Hūa)

Flos lonicerae is a honeysuckle flower belonging to Caprifoliaceae family. It is a widely used herb in China for the treatment of infection by exopathogenic wind-heat or epidemic febrile diseases.[11,14,27,28] The dried flower and buds of Flos Lonicerae have shown various pharmacological effects including anti-nociceptive, anti-diabetic, anti-tumor, antioxidant, anti-angiogenic, antipyretic, antiviral, and hepatoprotective activities.[6,29,30,31]Flos Lonicerae demonstrated anti-inflammatory properties through suppression of mediator release from the mast cells activated by secretagogues.[32] In addition, the n-butanol fraction containing Flos Lonicerae can alleviate inflammation better than celecoxib in carrageen- and croton oil-induced paw edema and ear edema.[29]Flos Lonicerae contains various active compounds that have marked anti-inflammatory effect, including luteolin (suppresses inflammatory mediator release by blocking NF-kB and MAPKs pathway activation in HMC-11 cells), chlorogenic acid (inhibits rat reflux esophagitis induced by pylorus and forestomach ligation), and loncerin (reduces edema by suppressing T cell proliferation, NO production from the macrophages, and shifting cellular immunity from Th1- toward Th2-type responses).[33,34,35]Flos Lonicerae has significant antimicrobial activity against diverse species of bacteria and fungi. It has inhibitory effect against H. pylori and Porphyromonas gingivalis,[15] and it treats candidal septic arthritis.[35] It also has antimicrobial effect against oral pathogens including Streptococcus mutans, Actinomyces viscosus, and Bacteroides melaninogenicus.[6]

Forsythia suspensa (連翹 Lián Qiào)

Forsythia suspensa is a flowering plant belonging to the family Oleaceae. Traditionally, it used to treat carbuncle, disperse lumps, and stagnation, and to expel wind and heat.[11,13,14] The fruit of F. suspensa has potent pharmacological actions such as antiviral, choleretic, antipyretic, hepatoprotective, antiemetic, and diuretic effects.[14,27]F. suspensa alleviates inflammation by reducing the anaphylactic antibodies, mast cell degranulation, and histamine release. It also significantly suppresses β-conglycinin–induced T lymphocyte proliferation and IL-4 synthesis.[36,37]F. suspensa fruit inhibits NO production and iNOS gene expression by its active components rengyolone, dibenzylbutyrolactone lignans, as well as its butanol fraction of the aqueous extract. It also inhibits TNF-α and COX-2 production.[38,39,40] Another bioactive agent, arctigenin, inhibits increase in capillary permeability and leukocyte recruitment into inflamed tissues, by reduction of the vascular leakage and cellular events through inhibition of production of inflammatory mediators such as NO and pro-inflammatory cytokines such as IL-1b, IL-6, TNF-α, and prostaglandin E2 (PGE2).[38,39,41] Moreover, F. suspensa inhibits NF-kB nucleus translocation through reduction in I-kappa-B (IkB) phosphorylation and suppression of NF-kB–regulated proteins, and also reduces the activation of MAPKs.[39,40,41] Various studies have reported the antimicrobial effect of F. suspensa. It has potent antibacterial activity against E. coli, Sta. aureus, Bacillus subtilis, Str. mutans, and Po. gingivalis and antifungal activity against Aspergillus flavus, Rhizopus stolonifer, Penicillium citrinum, Aspergillus niger, and Saccharomyces carlsbergensis.[6,42]F. suspensa suppresses influenza A virus–induced RANTES secretion by human bronchial epithelial cells to stop accumulation of inflammatory cells in the infective sites, which has been reported to play a crucial role in the progression of chronic inflammation and multiple sclerosis after viral infection.[27]

Isatidis folium (大青葉 Dà Qīng Yè)

Isatidis folium is a flowering plant belonging to the family Brassicaceae. The leaves of Isatidis Folium are traditionally used for the treatment of sore throat, redness of skin, and as an antipyretic.[13,14,27,43,44]Isatidis Folium has also been used to treat encephalitis, acute dysentery, hepatitis, measles, pneumonia, influenza, epidemic cerebrospinal meningitis, encephalitis B, viral pneumonia, mumps, and diabetics.[27,45,46] Tryptanthrin, an alkaloid isolated from Isatidis leaves, has shown anti-inflammatory effect due to its strong inhibitory effect on the COX-2 enzyme.[47] Several derivatives of hydroxycinnamic acid, including ferulic acid and sinapic acid, are also thought to be important to inhibit inflammation.[25]Isatidis Folium possesses valuable viricidal effect in the control of pseudorabies infection in swine.[48,49]

Radix Isatidis (板藍根 Bǎn Lán Gēn)

Isatidis radix belongs to the family Brassicaceae. Traditionally, it used to cool blood.[13,14,19] The dry root of Isatidis Radix has many pharmacological activities such as antibiotic, anti-diabetic, and immune-stimulating effects and is used to treat encephalitis B and viral infections.[48,50] Methanolic extracts of Isatidis Radix can significantly inhibit the release of inflammatory mediators from the macrophages, such as NO, PGE2, and pro-inflammatory cytokines.[51] Isatidis Radix has also been demonstrated to suppress the growth of E. coli and H. pylori and increases blood neutrophil phagocytosis of 32P-labeled Sta. aureus.[15,52,53] Syringic acid isolated from Isatidis Radix inhibited LPS-induced endotoxin shock.[51] Besides, Isatidis Radix is found to be clinically effective against the infections caused by various subtypes and strains of influenza viruses including Severe Acute Respiratory Syndrome (SARS).[44,50]

Viola yedoensis (紫花地丁 Zǐ Huā Dì Dīng)

Viola yedoensis is a flowering plant belonging to the violet family of Violaceae. Traditionally, it used to cool heat, and disinfect and detoxify.[11,13,14]V. yedoensis has several pharmacological effects including antibiotic, anti-inflammatory, and antipyretic activities. It can also be used for the treatment of skin diseases, i.e. eczema, impetigo, acne, pruritus, and cradle cap, and for upper respiratory tract infections with fever.[12,14] It has been reported to have antimicrobial activity against B. subtilis, Str. mutans, and Po. gingivalis.[54] It inhibits the replication of herpes simplex virus-1 and enterovirus 71 in the human neuroblastoma SK-N-SH cell line. Cyclotides from Viola are shown to be effective in inhibiting human immunodeficiency virus (HIV) replication.[50,55]

Pulsatilla radix (白頭翁 Bái Tóu Wēng)

Pulsatilla radix is a medicinal root plant of the Ranunculaceae. It used to cool heat, disinfect and detoxify, and clear damp-heat in TCM.[13,14] The root of Pulsatilla Radix has anti-inflammatory, antiparasitic, and antimicrobial action. It can treat dyspepsia, premenstrual tension, and psychosomatic disturbances.[14] A quinine-type compound, pulsaquinone, isolated from the aqueous ethanol extract of the roots of Pulsatilla Radix exhibited antimicrobial activities against an anaerobic non–spore-forming gram-positive bacillus, Pr. acnes, which is related to the pathogenesis of the inflamed lesions in a common skin disease, acne vulgaris.[56] Moreover, 4-hydroxy-3-methoxycinnamic acid of Pulsatilla Radix is found to have a selective growth inhibitor of the human intestinal bacteria, Clostridium perfringens and E. coli.[57]

Andrographis paniculata (穿心蓮 Chuān Xīn Lián)

Andrographis paniculata is also known as nemone chinensi and belongs to Acanthaceae family.[11] The active compounds isolated from An. paniculata, including diterpene, lactone, and andrographolide, have shown anti-inflammatory, anti-allergic, immune-stimulatory, and antiviral activities.[58,59]An. paniculata alleviates inflammation by inhibiting iNOS, TNF-α, IL-1b, IL-6, and IL-12 expression and NO production by down-regulation of p38MAPKs signaling pathways.[5,60] It also suppresses influenza A virus-induced RANTES secretion by human bronchial epithelial cells.[27]

Houttuynia cordata (魚腥草 Yú Xīng Cǎo)

Houttuynia cordata is one of the two species in the genus Houttuynia and belongs to the family Saururaceae.[14] It has many pharmacological effects including immune-stimulating, anti-inflammatory, antibiotic, antiviral, diuretic, analgesic, and hemostatic effects. It also used to treat pneumonia, bronchitis, colitis, urogenital tract infections, and chronic obstructive respiratory diseases, and topically to treat herpes simplex.[61]

Patrinia Herba (敗醬草 Bài Jiàn Cǎo)

Patrinia herba is a medicinal herb belongs to family of Valerianaceae.[12,14] It has antibiotic, hepatoprotective, sedating, and hypnotic effects, and it can be used to treat mumps.[14]Patrinia Herba can inhibit adjuvant-induced inflammation and hyperalgesia. In rats, it attenuates Freund’s adjuvant (CFA)–induced hyperalgesia and facilitates the recovery from hyperalgesia, and also reduces edema.[62]

CONCLUSION

Investigation of the functions of different Chinese herbs by modern research has allowed us to determine the importance of using Chinese herbs for treatment of many diseases. Various studies have revealed that HCCHs are used for treating inflammatory and microbial diseases due to their multiple active ingredients. Since inflammation is the result of interaction of various inflammatory mediators, HCCHs can exert anti-inflammatory effect through different mechanisms of action including inhibition of inflammatory cytokines and mediators, blocking of inflammatory signaling, and interfering with chemokines [Table 1]. Moreover, HCCHs have also shown antimicrobial effect through inhibition of microbial adherence to mucosal or epithelial surfaces, inhibition of endotoxin shock, and selective inhibition of microbial growth [Table 2]. Collectively, all the above mechanisms are likely to be important for the anti-inflammatory and antimicrobial activity of HCCHs. This review reveals the anti-inflammatory and antimicrobial effects of HCCHs, in general, from different aspects and through different mechanisms. This may be linked to their action of removing heat and fire and counteracting toxicity. Therefore, further studies are needed on the collection of HCCHs to find the detailed mechanism of action of herbs in this group and to determine whether their nature of clearing away heat is related to their anti-inflammatory and antimicrobial effects according to Chinese medical theory, rather than focusing on simple gradient or single herbs for the assessment of effective therapeutic drugs from HCCHs.

Table 1

Anti-inflammatory effects of HCCHs

Table 2

Antimicrobial effects of HCCHs

ACKNOWLEDGMENT

This study was supported by Tianjin University of Traditional Chinese Medicine (TUTCM).

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Antiparasitic activity of two Lavandula essential oils against Giardia duodenalis, Trichomonas vaginalis and Hexamita inflata.

By asmithers | Published December 20, 2015

Parasitol Res. 2006 Nov;99(6):722-8. Epub 2006 Jun 2.

 

Abstract

Two essential oils derived from Lavandula angustifolia and Lavandula x intermedia were investigated for any antiparasitic activity against the human protozoal pathogens Giardia duodenalis and Trichomonas vaginalis and the fish pathogen Hexamita inflata: all of which have significant infection and economic impacts. The study has demonstrated that low (< or = 1%) concentrations of L. angustifolia and L. x intermedia oil can completely eliminate T. vaginalis, G. duodenalis and H. inflata in vitro. At 0.1% concentration, L. angustifolia oil was found to be slightly more effective than L x intermedia oil against G. duodenalis and H. inflata. The potential applications are discussed.

PMID:
[PubMed – indexed for MEDLINE]
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Cod Liver Oil and Multiple Sclerosis Risk

By asmithers | Published December 17, 2015

Published in Neurology and

1 other channel

Journal Scan / Research · December 11, 2015

Image result for cod liver oil

TAKE-HOME MESSAGE

  • The authors report on data from the Norwegian portion of the multinational questionnaire-based case–control study Environmental Factors in Multiple Sclerosis (EnvIMS) with regard to timing of cod liver oil use in MS patients vs controls. In Norway, there is essentially no vitamin D contribution from sun exposure during the winter, and thus cod liver oil is routinely recommended. The Norway component of this study included 953 MS patients (maximum disease duration of 10 years) and 1717 controls. In a mail questionnaire, they were asked if they used cod liver oil or capsules at six different age ranges, the frequency, and the amount. Also assessed were other sources of vitamin D. Respondents who reported cod liver oil use during adolescence (aged 13–18 years) had a decreased risk of MS (OR, 0.67), while use during childhood or adulthood was not associated with change in risk. Additionally, there was an inverse relationship between the dose during adolescence and the risk of MS, with the lowest risk associated with a dose of 600 to 800 IU of vitamin D3 per day.
  • While these data would be subject to recall bias, the large doses of vitamin D commonly used and the low confounding from sun exposure make the results compelling.
    – Sarah Matteson Kranick, MD

Abstract

BACKGROUND

Low vitamin D levels have been associated with an increased risk of multiple sclerosis (MS), although it remains unknown whether this relationship varies by age.

OBJECTIVE

The objective of this paper is to investigate the association between vitamin D3 supplementation through cod liver oil at different postnatal ages and MS risk.

METHODS

In the Norwegian component of the multinational case-control study Environmental Factors In Multiple Sclerosis (EnvIMS), a total of 953 MS patients with maximum disease duration of 10 years and 1717 controls reported their cod liver oil use from childhood to adulthood.

RESULTS

Self-reported supplement use at ages 13-18 was associated with a reduced risk of MS (OR 0.67, 95% CI 0.52-0.86), whereas supplementation during childhood was not found to alter MS risk (OR 1.01, 95% CI 0.81-1.26), each compared to non-use during the respective period. An inverse association was found between MS risk and the dose of cod liver oil during adolescence, suggesting a dose-response relationship (p trend = 0.001) with the strongest effect for an estimated vitamin D3 intake of 600-800 IU/d (OR 0.46, 95% CI 0.31-0.70).

CONCLUSIONS

 

These findings not only support the hypothesis relating to low vitamin D as a risk factor for MS, but further point to adolescence as an important susceptibility period for adult-onset MS.

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