Shilajit attenuates behavioral symptoms of chronic fatigue syndrome by modulating the hypothalamic–pituitary–adrenal axis and mitochondrial bioenergetics in rats
Authors: Kumari Preeti
Sairam Krishnamurthy
Dinesh Kumar Surapaneni
Gangineni Ravi Teja
Muruganandam Veeraragavan
Sree Rama Shiva Shanker Adapa
Journal: Journal of Ethnopharmacology (2012)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Shilajit; chronic fatigue syndrome; mitochondrial bioenergetics; hypothalamus-pituitary-adrenal axis; rat model
Affiliations: Neurotherapeutics Lab, Department of Pharmaceutics, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005 U.P., India.

Abstract:  Ethnopharmacological relevance: Shilajit has been used as a rejuvenator for ages in Indian ancient traditional medicine and has been validated for a number of pharmacological activities. Aim of the study: The effect of processed shilajit which was standardized to dibenzo-α-pyrones (DBPs;0.43% w/w), DBP-chromoproteins (DCPs; 20.45% w/w) and fulvic acids (56.75% w/w) was evaluated in a rat model of chronic fatigue syndrome (CFS). The mitochondrial bioenergetics and the activity of hypothalamus-pituitary-adrenal (HPA) axis were evaluated for the plausible mechanism of action of shilajit. Materials and methods: CFS was induced by forcing the rats to swim for 15mins for 21 consecutive days. The rats were treated with shilajit (25, 50 and 100mg/kg) for 21 days before exposure to stress procedure. The behavioral consequence of CFS was measured in terms of immobility and the climbing period. The post-CFS anxiety level was assessed by elevated plus maze (EPM) test. Plasma corticosterone and adrenal gland weight were estimated as indices of HPA axis activity. Analysis of mitochondrial complex chain enzymes (Complex I, II, IV and V) and mitochondrial membrane potential (MMP) in prefrontal cortex (PFC) were performed to evaluate the mitochondrial bioenergetics and integrity respectively. Results: Shilajit reversed the CFS-induced increase in immobility period and decrease in climbing behavior as well as attenuated anxiety in the EPM test. Shilajit reversed CFS-induced decrease in plasma corticosterone level and loss of adrenal gland weight indicating modulation of HPA axis. Shilajit prevented CFS-induced mitochondrial dysfunction by stabilizing the complex enzyme activities and the loss of MMP. Shilajit reversed CFS-induced mitochondrial oxidative stress in terms of NO concentration and, LPO, SOD and catalase activities. Conclusion: The results indicate that shilajit mitigates the effects of CFS in this model possibly through the modulation of HPA axis and preservation of mitochondrial function and integrity. The reversal of CFS-induced behavioral symptoms and mitochondrial bioenergetics by shilajit indicates mitochondria as a potential target for treatment of CFS. 

Retracted: No

PubPeer comments:
  Whereas such innovations are conceived as methodological, they seem to share with all method the little ghosts of implicit assumptions. Elizabeth Converse, 1968 Others have criticized this paper in its rapid responses, and this review does not intend to recapitulate those criticisms. We note instead that the study methodology, which seems arbitrary, was not pre-registered, and therefore we have no confidence that the results, such as they were, were not shaped by post-hoc decision making.  Participants had 11 choices: whole foods, plant-based diet; keto diet; vegetarian diet; Mediterranean diet; pescatarian diet; Palaeolithic diet; low fat diet; low carbohydrate diet; high protein diet; other; none of the above. What was the rationale for those particular choices? Why, for example, was there no  meat and 3 vege , no  fast food - Pizza and or Burger based , which would possibly have secured many responses?  Before analyses, we selected dietary patterns with sufficient u2018yesu2019 responses (u2018yesu2019 response of at least 100 individuals). To increase precision, we analysed three dietary patterns after combining dietary patterns that are similar in terms of dietary intake. But we can see from the tables that ALL (combinations of) dietary patterns were far more similar than should have been the case in terms of dietary intake - and thus deduce that the use of dietary patterns may have obscured any meaningful variation in reported intakes,  We combined u2018whole foods, plant-basedu2019 diets and u2018vegetarianu2019 diets into one category (u2018plant-based dietsu2019, n=254).  Then, we combined u2018whole food, plant-basedu2019 diets, u2018vegetarianu2019 diets or u2018pescatarianu2019 diets into another category (u2018plant-based diets or pescatarian dietsu2019, n=294) to test if a spectrum of plant-based diets which include animal products are associated with COVID-19 severity. Due to the small number of cases (nine cases of moderate-to-severe COVID-19, 40 COVID-19 cases), we could not analyse pescatarian diets separately. We used plant-based diets to encompass plant-based diets and vegetarian diets, given that vegetarian diets are considered a subset of plant-based diets which minimise consumption of animal products (meat, fish, dairy).12 13 Lastly, we combined u2018low carbohydrateu2019 diets and u2018high proteinu2019 diets into another category (u2018low carbohydrate, high protein dietu2019, n=483) to evaluate whether these dietary patterns are associated with COVID-19 severity.  Why? Low carb diets are known to include keto diets, so why were these 2 categories not combined? High protein diets are - rightly or wrongly - commonly considered to include Paleolithic diets, so why were these 2 categories not combined? Instead, the combining of low carb with high protein gave us a group with a LOWER intake of butter and oil - that is, LESS added fat, than the rest of the cohort - which included low fat diets! It is not surprising that there were no real results; if symptoms associated with negative tests are excluded. There is no mention of how colds and flus were excluded as causes of symptoms in those without positive tests. It is frustrating to find intelligent commentary in the discussion:  Multiple viruses, such as coxsackievirus and influenza, have been shown to develop increased virulence due to changes in their genomes as a consequence of replicating in a nutritionally deficient host (eg, deficiency in selenium).25 26 Selenium may be an important nutrient to consider, considering its role in immunity . Indeed, but the data was not analysed in such a way as to answer this important question, one which to date meets all applicable Bradford Hill criteria, at all. Depending on circumstances vegetarian diets can supply lower selenium intakes than non-vegetarian diets, and in any case meat is a source of selenium, which is required for the health of animals but unnecessary for plant crops.[1] Also, the current study combines cohorts from 6 countries with wide differences in average soil selenium status, probably making it impossible to draw any conclusion at all on this question. It would appear that this paper has done nothing but muddy the waters, and provide the impression that those who, before Covid, were promoting  plant-based diets and condemning (their own unrealistic interpretation of)  low carb , which was structured with similar presumptions to the  low carb high protein composite in the current paper, have retained that bias. [1] Sobiecki, J.G. Vegetarianism and colorectal cancer risk in a low-selenium environment: effect modification by selenium status? A possible factor contributing to the null results in British vegetarians. Eur J Nutr 56, 1819u20131832 (2017). https: doi.org 10.1007 s00394-016-1364-0 ,