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Probiotic Reduces Depression and Alters Brain Activity in IBS

By asmithers | Published June 1, 2017
Published in Gastroenterology and
Journal Scan / Research · May 26, 2017
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TAKE-HOME MESSAGE

  • The effect of the probiotic Bifidobacterium longum NCC3001 on psychiatric symptoms was evaluated in 44 individuals with IBS and mild to moderate anxiety and depression in this randomized placebo-controlled trial. Compared with the placebo group, significantly more patients in the probiotic group had reduced depression scores, but not anxiety scores, at week 6.
  • The probiotic group also had increased quality-of-life scores and decreased limbic responses to negative stimuli on brain fMRI.

BACKGROUND & AIMS

Probiotics can reduce symptoms of irritable bowel syndrome (IBS), but little is known about their effects on psychiatric comorbidities. We performed a prospective study to evaluate the effects of Bifidobacterium longum NCC3001 (BL) on anxiety and depression in patients with IBS.

METHODS

We performed a randomized, double-blind, placebo-controlled study of 44 adults with IBS and diarrhea or a mixed-stool pattern (based on Rome III criteria) and mild to moderate anxiety and/or depression (based on the Hospital Anxiety and Depression scale) at McMaster University in Canada, from March 2011 to May 2014. At the screening visit, clinical history and symptoms were assessed and blood samples were collected. Patients were then randomly assigned to groups and given daily BL (n=22) or placebo (n=22) for 6 weeks. At week 0, 6 and 10, we determined patients’ levels of anxiety and depression, IBS symptoms, quality of life, and somatization using validated questionnaires. At week 0 and 6, stool, urine and blood samples were collected, and functional magnetic resonance imaging (fMRI) test was performed. We assessed brain activation patterns, fecal microbiota, urine metabolome profiles, serum markers of inflammation, neurotransmitters and neurotrophin levels.

RESULTS

At week 6, 14/22 patients in the BL group had reduction in depression scores of 2 points or more on the Hospital Anxiety and Depression scale, vs 7/22 patients in the placebo group (P=.04). BL had no significant effect on anxiety or IBS symptoms. Patients in the BL group had a mean increase in quality of life score compared with the placebo group. The fMRI analysis showed that BL reduced responses to negative emotional stimuli in multiple brain areas, including amygdala and fronto-limbic regions, compared with placebo. The groups had similar fecal microbiota profiles, serum markers of inflammation, and levels of neurotrophins and neurotransmitters, but the BL group had reduced urine levels of methylamines and aromatic amino acids metabolites. At week 10, depression scores were reduced in patients given BL vs placebo.

CONCLUSION

In a placebo-controlled trial, we found that the probiotic BL reduces depression but not anxiety scores and increases quality of life in patients with IBS. These improvements were associated with changes in brain activation patterns that indicate that this probiotic reduces limbic reactivity.

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Herbal Therapy Is Equivalent to Rifaximin for the Treatment of Small Intestinal Bacterial Overgrowth

By asmithers | Published April 22, 2017

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Link to Publisher's site
Glob Adv Health Med. 2014 May; 3(3): 16–24.
Published online 2014 May 1. doi:  10.7453/gahmj.2014.019
PMCID: PMC4030608

Herbal Therapy Is Equivalent to Rifaximin for the Treatment of Small Intestinal Bacterial Overgrowth

Victor Chedid, MD, Sameer Dhalla, MD, John O. Clarke, MD, Bani Chander Roland, MD, Kerry B. Dunbar, MD, Joyce Koh, MD, Edmundo Justino, MD, Eric Tomakin, RN, and Gerard E. Mullin, MDcorresponding author
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Abstract

Objective:

Patients with small intestine bacterial overgrowth (SIBO) have chronic intestinal and extraintestinal symptomatology which adversely affects their quality of life. Present treatment of SIBO is limited to oral antibiotics with variable success. A growing number of patients are interested in using complementary and alternative therapies for their gastrointestinal health. The objective was to determine the remission rate of SIBO using either the antibiotic rifaximin or herbals in a tertiary care referral gastroenterology practice.

Design:

One hundred and four patients who tested positive for newly diagnosed SIBO by lactulose breath testing (LBT) were offered either rifaximin 1200 mg daily vs herbal therapy for 4 weeks with repeat LBT post-treatment.

Results:

Three hundred ninety-six patients underwent LBT for suspected SIBO, of which 251 (63.4%) were positive 165 underwent treatment and 104 had a follow-up LBT. Of the 37 patients who received herbal therapy, 17 (46%) had a negative follow-up LBT compared to 23/67 (34%) of rifaximin users (P=.24). The odds ratio of having a negative LBT after taking herbal therapy as compared to rifaximin was 1.85 (CI=0.77-4.41, P=.17) once adjusted for age, gender, SIBO risk factors and IBS status. Fourteen of the 44 (31.8%) rifaximin non-responders were offered herbal rescue therapy, with 8 of the 14 (57.1%) having a negative LBT after completing the rescue herbal therapy, while 10 non-responders were offered triple antibiotics with 6 responding (60%, P=.89). Adverse effects were reported among the rifaximin treated arm including 1 case of anaphylaxis, 2 cases of hives, 2 cases of diarrhea and 1 case of Clostridium difficile. Only one case of diarrhea was reported in the herbal therapy arm, which did not reach statistical significance (P=.22).

Conclusion:

SIBO is widely prevalent in a tertiary referral gastroenterology practice. Herbal therapies are at least as effective as rifaximin for resolution of SIBO by LBT. Herbals also appear to be as effective as triple antibiotic therapy for SIBO rescue therapy for rifaximin non-responders. Further, prospective studies are needed to validate these findings and explore additional alternative therapies in patients with refractory SIBO.

Key Words: Irritable bowel syndrome (IBS), rifaximin, Antibiotics, Small Intestine Bacterial Overgrowth (SIBO), Dysbiosis, Complementary and Alternative Medicine (CAM), Herbal Therapies
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Antimicrobial efficacy of five essential oils against oral pathogens: An in vitro study

By asmithers | Published January 27, 2016

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Eur J Dent. 2013 Sep; 7(Suppl 1): S71–S77.
Nilima Thosar,1 Silpi Basak,2 Rakesh N. Bahadure,3 and Monali Rajurkar2
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This article has been cited by other articles in PMC.

Abstract

Objectives:

This study was aimed to find out the minimum inhibitory concentration (MIC) of five essential oils against oral pathogens and to find out the minimum bactericidal concentration (MBC) and minimum fungicidal concentration (MFC) of five essential oils against oral pathogens.

Materials and Methods:

The antimicrobial activities by detecting MIC and MBC/MFC of five essential oils such as tea tree oil, lavender oil, thyme oil, peppermint oil and eugenol oil were evaluated against four common oral pathogens by broth dilution method. The strains used for the study were Staphylococcus aureusATCC 25923, Enterococcus fecalis ATCC 29212, Escherichia coli ATCC 25922 and Candida albicans ATCC 90028.

Results:

Out of five essential oils, eugenol oil, peppermint oil, tea tree oil exhibited significant inhibitory effect with mean MIC of 0.62 ± 0.45, 9.00 ± 15.34, 17.12 ± 31.25 subsequently. Mean MBC/MFC for tea tree oil was 17.12 ± 31.25, for lavender oil 151.00 ± 241.82, for thyme oil 22.00 ± 12.00, for peppermint oil 9.75 ± 14.88 and for eugenol oil 0.62 ± 0.45. E. fecalis exhibited low degree of sensitivity compared with all essential oils.

Conclusion:

Peppermint, tea tree and thyme oil can act as an effective intracanal antiseptic solution against oral pathogens.

Keywords: Antimicrobial activity, essential oils, oral pathogens

INTRODUCTION

The spread of drug resistant pathogens is one of the most serious threats to successful treatment of microbial diseases. Essential oils and other extracts of plants have evoked interest as sources of natural products.[1] Essential oils also called volatile oils, are aromatic oily liquids obtained from plant materials such as flowers, buds, seeds, leaves, twigs, bark, herbs, wood, fruits and roots. An estimated 3000 essential oils are known, of which 300 are commercially important in the fragrance market.[2] The antimicrobial activity of essential oils is due to a number of small terpenoids and phenol compounds.[3] Several of these are classified as generally recognized as safe.[4] Essential oils such as tea tree oil, lavender oil, thyme oil, peppermint oil and eugenol oil have been traditionally used by people for various purposes in different parts of the world.

The root canal environment after chemomechanical treatment becomes unfavorable for microorganisms; there is reduced oxygen tension, limited nutrient availability and antimicrobial agents that act as driving forces in survival balance of bacteria in the root canal system.[5] Root canal dentinal tubules harbor microorganisms; also bacterial biofilm may be present at the apical portion of root canal and extra-radicular regions.[6] Therefore, irrigation with a broad spectrum antiseptic substances and interappointment intracanal medication has become a standard regimen in root canal therapy. Many species and herbs exert antimicrobial activity due to their essential oil fractions. For thousands of years clove oil (eugenol) has been used in dentistry. Eugenol has been used topically in dental practice to relieve pain arising from a variety of sources, including pulpits and dentinal hypersensitivity. Interestingly, eugenol exhibits irritant action in addition to its analgesic effect as found in certain studies.[7] So in search of plant essential oils possessing antimicrobial activity, this study was undertaken to determine in vitro, antimicrobial action of eugenol, thyme oil, tea tree oil, peppermint oil and lavender oil against four pathogenic oral micro-organisms.

In this study, it was aimed to detect in vitro antimicrobial efficacy of five essential oils against oral pathogens. Firstly, it was aimed to find out the minimum inhibitory concentration (MIC) of five essential oils against oral pathogens. Secondly, it was aimed to find out the minimum bactericidal concentration (MBC) and minimum fungicidal concentration (MFC) of five essential oils against oral pathogens.

MATERIALS AND METHODS

We used five essential oils as following:

Tea tree oil, lavender oil, thyme oil, peppermint oil, and eugenol oil.

Essential oils

Five essential oils such as tea tree oil, lavender oil, thyme oil, peppermint oil and eugenol oil were obtained from Arromatantra, Mumbai, India. These oils were selected based on the literature survey and their use in traditional medicine. Quality of oils was ascertained to be pure.

Test organism

Microorganisms were obtained from the Department of Microbiology, Jawaharlal Nehru Medical College, Wardha, Maharashtra, India. The strains used for the study were Staphylococcus aureus(ATCC 25923), Enterococcus fecalis (ATCC 29212), Escherichia coli (ATCC 25922) and Candida albicans (ATCC 90028). Stock cultures of bacteria were used for the study.

MIC and MBC/MFC determination

The antimicrobial activities by detecting MIC of five essential oils such as tea tree oil, lavender oil, thyme oil, peppermint oil and eugenol oil were evaluated against four common oral pathogens by broth dilution method [Figure 1].[8] MBC was detected by subculturing onto blood agar from the tube showing no turbidity (i.e., MIC) and the next tube to it. The blood agar plates were incubated at 37°C overnight for 18-20 h and on the next day the readings were taken. For MFC, subcultures were done on Sabouraud’s dextrose agar plates following the same procedure [Figures ​[Figures22–5]. Various concentrations of five essential oils used against oral pathogens were in doubling dilutions [Table 1]. Results were analyzed statistically by using the one-way analysis of variance.

Figure 1

Minimum inhibitory concentration of thyme oil forStaphylococcus aureus

Figure 2

Minimum bactericidal concentration for Enterococcus fecalis

Figure 5

Minimum fungicidal concentration for Candida albicans

Table 1

Different concentrations of essential oils against common oral pathogens

Figure 3

Minimum bactericidal concentration for Escherichia coli

Figure 4

Minimum bactericidal concentration for Stapholococcus aureus

RESULTS

Out of five essential oils, eugenol oil, peppermint oil, tea tree oil exhibited significant inhibitory effect [Table 2] with mean MIC of 0.62 ± 0.45, 9.00 ± 15.34, 17.12 ± 31.25 subsequently. There was no statistical significant difference in five essential oils (F = 1.61, P = 0.221) [Table 3]. Mean MBC/MFC for tea tree oil was 17.12 ± 31.25, for lavender oil 151.00 ± 241.82, for thyme oil 22.00 ± 12.00, for peppermint oil 9.75 ± 14.88 and for eugenol oil 0.62 ± 0.45 (F = 1.30, P = 0.312) [Table 4]. Eugenol showed antimicrobial activity at the lowest concentration compared with all essential oils i.e., for C. albicans: MIC, MFC: 0.1 μl/ml, for S. aureus: MIC, MBC: 0.4 μl/ml, for E. coli and for E. facelis: MIC, MBC: 1 μl/ml respectively [Figures ​[Figures22–5].

Table 2

MIC and MBC/MFC of five essential oils (μl/ml)

Table 3

MIC of five essential oils

Table 4

MBC/MFC of five essential oils

DISCUSSION

Tea tree oil is the volatile essential oil derived mainly from the Australian native plant, Melaleuca alternifolia. Tea tree oil is composed of terpene hydrocarbons, mainly monoterpenes, sesquiterpenes and their associated alcohols. Terpenes are volatile, aromatic hydrocarbons and may be considered polymers of isoprene, which has the formula C5H8.[9] Antibacterial activity in literature appeared from 1940 to 1980.[10,11,12,13] From the early 1990s onward, many reports describing the antimicrobial activity of tea tree oil appeared in the scientific literature.[9]

Antimicribial activity of tea tree oil is due to terpinen-4-ol, α-terpineol and 1,8-, which cause leakage of 260 nm-light absorbing material and render cells susceptible to sodium chloride.[14] Thus, tea tree oil causes lysis and the loss of membrane integrity and function manifested by the leakage of ions and the inhibition of respiration.[9] Antimicrobial resistant isolates of S. aureus,[15,16] C. albicans,[17] and E. faecium[18,19] have been found to have in vitro susceptibilities to tea tree oil. In this study, antimicrobial effect of tea tree oil for C. albicans (MIC: 0.5 μl/ml, MFC: 0.5 μl/ml) was found at the lowest concentration followed by S. aureus (MIC: 1 μl/ml, MBC: 2 μl/ml) and E. coli (MIC: 2 μl/ml, MBC: 2 μl/ml), lastly E. faecalis (MIC: 64 μl/ml, MBC: 64 μl/ml).

Much of pure lavender oil (Lavandula officianalis L. angustifolia [Miller] or L. vera-Labiatae/Lamiaceae) comes from Balkans. France still produces the finest quality, but production there is tumbled with the advent of the hybrid. Essential oil of lavender is obtained from the flowering tops by steam distillation method. Its principal constituents include monoterpens, Oxides, linalyl and geranyle esters, geraniol, linalool etc., It has variety of properties, which includes that it is anti-depressant, hypotensive, soothing, alleviates stress, anxiety and general debility. It is antiseptic and anti-inflammatory for colds, flu and sinusitis and throat infections. It is balancing, antiseptic, anti-inflammatory and regenerative; soothes acne, eczema, dandruff, hair loss, head lice, diaper/nappy rash, sunburn, insect bites and boils; relieves Athlete’s foot and herpes simplex. It has cleansing and calming effect; helps colic, dyspepsia, indigestion, flatulence and gastroenteritis. It is sedative and decongestant; lowers blood pressure reduces palpitations. It has musculo-analgesic and anti-inflammatory effect in neuritis, neuralgia, muscular sprains, cramps, aches and pains. It is also used in inhalations, vaporizers, compresses, bath application or massage.[20] In the study of Zuzarte et al., 2009[21] antifungal activity of lavender oil was found with MIC values of 0.32-0.64 μl/ml. In the study of Zuzarte (2011)[22] candida species, were found to be sensitive to lavender oil with MIC of 0.64 μl/ml. In our study, it was achieved with a higher concentration i.e., 8 μl/ml for C. albicans. S. aureus and E. faecalis were susceptible at the concentration of MIC: 32 μl/ml and MBC: 64 μl/ml respectively. E. coli was least susceptible with MIC: 128 μl/ml and MBC: 512 μl/ml.

The name thyme actually comes from the Greek word “thymos,” meaning small because of the fragrance of the plant. Thyme belongs to over 300 species of hardy, perennial herbaceous plants and shrubs that are native to Europe, particularly around Mediterranian. It is one of the Hippocrates 400 simple remedies. Essential oil of thyme (Thymus Spp, T. citriodorits, T. vulgaris-Labiatae/Lamiaceae) is obtained from the leaves and flowering tops by steam distillation method. Its principal constituents include 20-40% thymol and carvacrol with borneol, cineol, linalool, menthone, B-cymene, pinene and triterpenic acid. Thyme oil is a tonic stimulant and stomachic and digestive relieves gastritis, enterocolitis and mouth thrush. It is useful for respiratory infections, asthma and bronchitis. It is effective for treating swelling provoked by gout or rheumatic problems, for joint pains, backache and sciatica. Thyme oil is also useful for urinary and vaginal infections, endometritis (candida), prostrates and vaginitis.[20] Thyme oil exhibits antibacterial activity and has been useful in dental practice.[23] A component of thyme, known as thymol, appears to inhibit growth of oral pathogens in the mouth and in combination with other essential oils, may reduce dental caries.[24,25] In patients with orthodontic brackets, a dental varnish containing thymol reduced the proportion ofStreptococcus mutans in supragingival plaque near the bracket.[26] Thymol is one of the essential oils with antibacterial effects found in Listerine.[27] In the study of Gislene et al., 2000[28] Hili et al.,1997[29] and Nzeako et al., 2006[30] thyme and clove oil possessed antimicrobial activity againstS. aureus, E. coli and C. albicans at various concentration of the extracts. In our study, antimicrobial susceptibility in order of sequence for thyme oil was E. coli with MIC: 2 μl/ml, MBC: 8 μl/ml, C. albicans with MIC, MFC: 16 μl/ml, E. faecalis with MIC, MBC: 32 μl/ml and S. aureus with MIC, MBC: 32 μl/ml respectively.

Essential oil of peppermint (Mentha piperita-Lamiaceae/Labiatae) is cultivated on a wide scale in Europe, USA and Japan. It is extensively used in toiletry, food and pharmaceutical industries. A variety of products ranging from toothpastes, mouthwashes and digestive tablets to sweets, ice cream and liquors are flavored with peppermint. Essential oil of peppermint is obtained from the leaves by steam distillation method. Its principal constituents include monoterpinic alcohols mainly menthol (38-48%), ketones mainly menthones (20-30%), some monoterpens and oxides. It is a good antiseptic, antibacterial and antiviral. It has light, clean, refreshing aroma and is a good insect repellant. It has stimulating and strengthening effect; in treatment of shock, helpful for neuralgia and relief of general debility, headaches and migraines. It has antiseptic and anti-spasmodic effect; in reducing mucus and relieving coughs, sinusitis, throat infections, colds, flu, asthma and bronchitis. It is also used in inhalations, baths or applications. It has got cooling and cleansing effect; soothes itchy skin, relieves inflammation. It has soothing and anti-spasmodic effect; relieves acidity, heartburn, diarrhea, indigestion and flatulence, also effective for travel sickness and nausea. It has cooling effect in case of varicose veins and hemorrhoids.[20] Peppermint oil makes the mouth feel fresh and of course, makes the formula taste good. Peppermint oil can also increase salivation, which is useful because dry mouth may result in halitosis.[31] In our study, antimicrobial effect was achieved at the concentration of 0.5 μl/ml for C. albicans and at the concentration of 32 μl/ml for E. coli, S. aureus, E. faecalis (32 μl/ml).

The clove plant grows in warm climates and is cultivated commercially in Tanzania, Sumatra, the Maluku (Molucca) Islands and South America. The tall evergreen plant grows up to 20 m and has leathery leaves. The clove spice is the dried flower bud of Eugenia caryophyllata species. Essential oils are obtained from the buds, stems and leaves by steam distillation. The buds or cloves are strongly aromatic. Clove buds yield approximately 15-20% of a volatile oil that is responsible for the characteristic smell and flavor. The bud also contains a tannin complex, a gum and resin and a number of glucosides of sterols. The principal constituent of distilled clove bud oil (60-90%) is eugenol (4-allyl-2-methoxyphenol). The oil also contains about 10% acetyleugenol and small quantities of gallic acid, sesquiterpenes, furfural and vanillin and methyl-n-amyl ketone. Other constituents include flavonoids, carbohydrates, lipids, oleanolic acid, rhamnetin and vitamins.[32]

Eugenol is widely used and well-known for its medicinal properties. Traditional uses of clove oil include the use in dental care, as an antiseptic and analgesic.[33] It is active against oral bacteria associated with dental caries and periodontal disease[34] and effective against a large number of other bacteria[35,36,37,38] and virus.[39] Previous studies have reported biological activities of eugenol including antifungal,[40,41,42] anti-carcinogenic,[43] anti-allergic,[44,45] anti-mutagenic activity,[46] antioxidant[47] and insecticidal[48] properties. In our study, eugenol oil showed antimicrobial activity at the lowest concentration against all organisms compared with all essential oils such as for C. albicans with MIC, MFC: 0.1 μl/ml, for S. aureus with MIC, MBC: 0.4 μl/ml, forE. coli and for E. facelis with MIC, MBC: 1 μl/ml respectively.

CONCLUSION

Hence, this study concludes that apart from traditional use of eugenol, antibacterial effects of essential oils such as peppermint oil, tea tree oil, thyme oil also can provide an effective intracanal antiseptic solution against oral pathogens.

Footnotes

Source of Support: Nil.

Conflict of Interest: None declared

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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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