Octanoic acid a major component of widely consumed medium-chain triglyceride ketogenic diet is detrimental to bone.

Octanoic acid is a medium-chained saturated fatty acid found abundantly in the ketogenic dietary supplements containing medium chained triglycerides (MCT) along with decanoic acid. The MCT ketogenic diet is commonly consumed for weight loss but has also showcased neuroprotective potential against neurodegenerative disorders. However, recent clinical findings have reported a critical disadvantage with the long-term consumption of ketogenic diet i.e. bone loss. The following study was employed to investigate whether the two major components of MCT diet also possess bone loss potential as observed with classical ketogenic diet. Swiss albino mice aged between 10 and 12 weeks, were divided into 3 treatment groups that were administered with oral suspensions of octanoic acid, decanoic acid and a combination of both for 4 weeks. Bone specific markers, microarchitectural parameters, using micro computed tomography, and biomechanical strength were analyzed. Remarkably deleterious alterations in the trabecular bone microarchitecture, and on bone markers were observed in the octanoic acid treated groups. Our results suggest significant negative effects on bone health by octanoic acid. These findings require further investigation and validation in order to provide significant clinically relevant data to possibly modify dietary composition of the MCT ketogenic diet.

A systematic review on Piper longum L.: Bridging traditional knowledge and pharmacological evidence for future translational research.

ETHNOPHARMACOLOGICAL RELEVANCE: Piper longum, commonly referred as 'Pippali', has found its traditional use in India, Malaysia, Singapore and other South Asian countries as an analgesic, carminative, anti-diarrhoeic, immunostimulant, post childbirth to check postpartum hemorrhage and to treat asthma, insomnia, dementia, epilepsy, diabetes, rheumatoid arthritis, asthma, spleen disorder, puerperal fever, leprosy etc. AIM OF THE REVIEW: This review offers essential data focusing on the traditional use, phytochemistry and pharmacological profile of Piper longum thereby identifying research gaps and future opportunities for investigation on this plant. MATERIALS AND METHODS: This systematic survey was accomplished as per the PRISMA guidelines. The information was collected from books, and electronic search (PubMed, Science Direct, Lilca and Scielo) during 1967-2019. RESULTS: Many phytochemicals have been identified till date, including alkaloids as its major secondary metabolites (piperine and piperlongumine), essential oil, flavonoids and steroids. These exhibit a wide range of activities including anti-inflammatory, analgesic, anti-oxidant, anti-microbial, anti-cancer, anti-parkinsonian, anti-stress, nootropic, anti-epileptic, anti-hyperglycemic, hepatoprotective, anti-hyperlipidemic, anti-platelet, anti-angiogenic, immunomodulatory, anti-arthritic, anti-ulcer, anti-asthmatic, anthelmintic action, anti-amebic, anti-fungal, mosquito larvicidal and anti-snake venom. CONCLUSION: Amongst various activities, bioscientific clarification in relation to its ethnopharmacological perspective has been evidenced mainly for anti-amebic, anthelminthic, anti-tumor and anti-diabetic activity. However, despite traditional claims, insufficient scientific validation for the treatment of insomnia, dementia, epilepsy, rheumatoid arthritis, asthma, spleen disorder, puerperal fever and leprosy, necessitate future investigations in this direction. It is also essential and critical to generate toxicological data and pharmacokinetics on human subjects so as to confirm its conceivable bio-active components in the body.

Behavioral Experimental Paradigms for the Evaluation of Drug's Influence on Cognitive Functions: Interpretation of Associative, Spatial/Nonspatial and Working Memory.

BACKGROUND: Currently, a large number of people throughout the world are affected by neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease which appear with a lapse in recall, attention and altered cognitive functions. Learning and memory, the fundamental indices defining cognitive functions, are the complex psychological processes governing acquisition, consolidation, and retrieval of stored information. These processes are synchronized by the coordination of various parts of the brain including hippocampus, striatum and amygdala. OBJECTIVE: The present review is centered on different behavioral paradigms in rodents interpreting learning and memory both explicitly and implicitly. Furthermore, it is also emphasizing on the interaction of various brain structures during different stages of associative, spatial and non-spatial memory. METHODS: We embarked on an objective review of literature relevant to screening methods for evaluation of drug's influence on a wide range of cognitive functions (learning and memory) as well as the underlying mechanism responsible for modulation of these functions. RESULTS: Our review highlighted the behavioral paradigms based on associative, spatial/nonspatial and working memory. The cited research acknowledged the hippocampal and striatal control on learning and memory. CONCLUSION: Since the neurodegenerative disorders and dementia have continuously been increasing, a wide range of therapeutic targets have been developed at the cellular and molecular level. This arises the necessity of screening of these targets in different cognitive behavioral paradigms which reflect their memory enhancing potential. The understanding of behavioral models and the involvement of brain structures in cognitive functions highlighted in the present review might be helpful to advance therapeutic interventions.

Aromatase inhibition by letrozole attenuates kainic acid-induced seizures but not neurotoxicity in mice.

Evidence shows neurosteroids play a key role in regulating epileptogenesis. Neurosteroids such as testosterone modulate seizure susceptibility through its transformation to metabolites which show proconvulsant and anticonvulsant effects, respectively. Reduction of testosterone by aromatase generates proconvulsant 17-ß estradiol. Alternatively, testosterone is metabolized into 5α-dihydrotestosterone (5α-DHT) by 5α-reductase, which is then reduced by 3α-hydroxysteroid oxidoreductase enzyme (3α-HSOR) to form anticonvulsant metabolite 3α-androstanediol (3α-Diol), a potent GABAA receptor modulating neurosteroid. The present study evaluated whether inhibition of aromatase inhibitor letrozole protects against seizures and neuronal degeneration induced by kainic acid (KA) (10 mg/kg, i.p.) in Swiss albino mice. Letrozole (1 mg/kg, i.p.) administered one hour prior to KA significantly increased the onset time of seizures and reduced the% incidence of seizures. Pretreatment with finasteride, a selective inhibitor of 5α-reductase and indomethacin, a selective inhibitor of 3α-hydroxysteroid oxidoreductase enzyme (3α-HSOR), reversed the protective effects of letrozole in KA-induced seizures in mice. Microscopic examination using cresyl violet staining revealed that letrozole did not modify KA-induced neurotoxicity in the CA1, CA3 and DG region of the hippocampus. Letrozole treatment resulted in the reduced levels of 17-ß estradiol and elevated the levels of 5α-dihydrotestosterone (DHT) and 3α-Diol in the hippocampus. Finasteride and indomethacin attenuated letrozole-induced elevations of 5α-DHT and 3α-Diol. Our results indicate the potential anticonvulsant effects of letrozole against KA-induced seizures in mice that might be mediated by inhibiting aromatization of testosterone to 17ß-estradiol, a proconvulsant hormone and by redirecting the synthesis to anticonvulsant metabolites, 5α-DHT and 3α-Diol. Acute aromatase inhibition, thus, might be used as an adjuvant in the treatment of status epilepticus and can be pursued further.

A review on therapeutic potentials of Trigonella foenum graecum (fenugreek) and its chemical constituents in neurological disorders: Complementary roles to its hypolipidemic, hypoglycemic, and antioxidant potential.

OBJECTIVES: The growing rate of neurological disorders is a major concern in today's scenario. Today's research is focusing on therapeutic interventions providing benefits in these disorders. Presently, drugs of natural origin have gained more interest for the treatment of central nervous system disorders for their efficacy and less/ no side effects. This review is emphasizing the cited roles of Trigonella foenum graecum (fenugreek) and its constituents in different neurological manifestations. METHOD: A review of the literature, relevant to the role of fenugreek and its major constituents including saponins and alkaloids in different neurological aspects and in delineating the health benefits, was conducted. RESULTS: The cited research acknowledged that fenugreek and its constituents exert positive influence on neurological health. Few studies have reported the beneficial role of fenugreek and its constituents like trigonelline in pathological symptoms of Alzheimer's disease. Similarly, other studies evidenced the neuroprotective, antidepressant, antianxiety as well as modulatory effect on cognitive functions and Parkinson's disease. DISCUSSION: Large populations are the sufferers of the neurological disorders, pointing the need for investigation of such therapeutic interventions which target and delay the underlying pathological hallmarks and exert positive influence on different neurological health problems. Hypolipidemic, hypoglycemic, antioxidant, and immunomodulatory effects of fenugreek and its constituents with their potential role in various neurological disorders were already reported. In future, it would be of even greater interest to further develop more effective dosage, supplementation period, and to evaluate the therapeutic potentials of fenugreek and its constituents in neurological disorders by exploring underlying cellular and molecular mechanisms.

Resveratrol suppressed seizures by attenuating IL-1ß, IL1-Ra, IL-6, and TNF-α in the hippocampus and cortex of kindled mice.

OBJECTIVE: There is an urge to identify new molecules which can modulate process of epileptogenesis, since currently available drugs act symptomatically and one-third of the patients remain refractory to the disease. Hence, the present study was conducted to evaluate the effects of Resveratrol (RESV) on epileptogenesis in pentylenetetrazole (PTZ)-induced kindling in mice. METHOD: Swiss albino mice were administered RESV (10, 20 and 40 mg/kg,p.o) in acute study. On the seventh day animals were subjected to various neurological and neurobehavioral tests viz, Increasing Current Electroshock Test (ICES), PTZ-induced seizures, passive avoidance response, and elevated plus maze test. For the development of kindling PTZ was administered in a dose of 25 mg/kg, i.p. on every alternate day and RESV in all the three doses was administered daily. Seizure score was continuously monitored till the development of kindling and cognition tests were performed in the end of the study. The animals were sacrificed and levels of inflammatory biomarkers viz., IL-1ß, interleukin-1 receptor antagonist (IL1-Ra), IL-6, and TNF-α were assessed in the hippocampus and cortex of the kindled animals. RESULTS: RESV in all three doses increased the seizure threshold to hind limb extension in the ICES test. RESV in all the tested doses suppressed the development of kindling and reduced the levels of IL-1ß, IL1-Ra, IL-6, and TNF-α in kindled mice. CONCLUSION: RESV suppressed the development of kindling in mice and decreased the levels of inflammatory biomarkers in their hippocampus. RESV modified brain inflammation during epileptogenesis and found to possess nootropic activity in the kindled mice.

Innovative Targets For Asthma And COPD: Exploring The Existing And Screening The New!!

The inadequate benefits of the existing therapies and the new insights into the pathophysiology of inflammatory airway diseases like chronic obstructive pulmonary disease (COPD) and asthma have led to the breakthrough of newer targets and innovative compounds as the treatment alternatives. The enhanced interpretation of immune cell signalling and signal transduction pathways at the molecular level involved in this process allows the selection of new therapeutic targets and designing of new molecules to combat such multifactorial diseases. Pertaining to the marked variability in type of inflammation observed in their disease phenotypes, the blockade of a particular receptor or mediator yielding strong restorative effect in one patient may not be significant to other. Therefore, their management requires the prompt and phenotype specific optimized drug therapies and development of new and improved molecular compounds targeting the immune cell signalling. This whole process including the approval of such compounds as the standard drug therapies is time taking, expensive and complicated task. It ranges from the selection of novel anti-inflammatory drug target to the final approval of biologically active restorative molecules. Grounded on this, the current review gives a comprehensive idea of the basic immunological network involved in these inflammatory airway diseases at the cellular level along with the discussion of their potential therapeutic targets. It also follows brief over viewing of the drug development process generally employed for the exploration of such innovative targets leading to the discovery of novel anti-inflammatory molecules for these inflammatory airway diseases.

Raloxifene preserves phenytoin and sodium valproate induced bone loss by modulating serum estradiol and TGF-ß3 content in bone of female mice.

Antiepileptic drugs (AEDs)-induced adverse consequences on bone are now well recognized. Despite this, there is limited data on the effect of anti-osteoporotic therapies on AEDs-induced bone loss. We hypothesize that estrogen deprivation following phenytoin (PHT) and sodium valproate (SVP) therapy could lead to adverse bony effects. Both PHT and SVP inhibit human aromatase enzyme and stimulate microsomal catabolism of oestrogens. Estrogen deficiency states are known to reduce the deposition of transforming growth factor-ß (TGF-ß3), a bone matrix protein, having anti-osteoclastic property. Thus, an attempt was made to investigate the effect of raloxifene, a selective oestrogen receptor modulator, in comparison with calcium and vitamin D3 (CVD) supplementation, on PHT and SVP-induced alterations in bone in mice and to unravel the role of estradiol and TGF-ß3 in mediation of bony effects by either AEDs or raloxifene. Further, the effect of raloxifene on seizures and on the antiepileptic efficacy of PHT and SVP was investigated. Swiss strains of female mice were treated with PHT (35 mg/kg, p.o.) and SVP (300 mg/kg, p.o.) for 120 days to induce bone loss as evidenced by reduced bone mineral density (BMD) and altered bone turnover markers (BTMs) in lumbar bones (alkaline phosphatase, tartarate resistant acid phosphatase, hydroxyproline) and urine (calcium). The bone loss was accompanied by reduced serum estradiol levels and bone TGF-ß3 content. Preventive and therapeutic treatment with raloxifene ameliorated bony alterations and was more effective than CVD. It also significantly restored estradiol and TGF-ß3 levels. Deprived estrogen levels (that in turn reduced lumbar TGF-ß3 content) following PHT and SVP, thus, might represent one of the various mechanisms of AEDs-induced bone loss. Raloxifene preserved the bony changes without interfering with antiepileptic efficacy of these drugs, and hence raloxifene could be a potential therapeutic option in the management of PHT and SVP-induced bone disease if clinically approved.

Histamine H3 receptor antagonism by ABT-239 attenuates kainic acid induced excitotoxicity in mice.

The multifaceted pathogenesis of temporal lobe epilepsy (TLE) offers a number of adjunctive therapeutic prospects. One such therapeutic strategy could be targeting H3 receptor (H3R) by selective H3R antagonists which are perceived to have antiepileptic and neuroprotective potential. Kainic acid (KA) induced seizure, a reliable model of TLE, triggers epileptogenic events resulting from initial neuronal death and ensuing recurring seizures. The present study aimed to determine whether pre-treatment with ABT-239, a novel H3R antagonist, and its combinations with sodium valproate (SVP) and TDZD-8 (glycogen synthase kinase-3ß (GSK3ß) inhibitor) can prevent the excitotoxic events in mice exposed to KA (10 mg/kg i.p.). ABT-239 (1 and 3 mg/kg i.p.) significantly attenuated KA-mediated behavioural and excitotoxic anomalies and restored altered expression of Bax, cleaved caspase-3, phospho-Akt (Ser473) and cAMP response element binding protein (CREB). Surprisingly, restoration of Bcl2 and phospho-GSK3ß (Ser9) by ABT-239 did not reach the level of statistical significance. Co-administration of ABT-239 (1 and 3 mg/kg) with a sub-effective dose of SVP (150 mg/kg i.p.) yielded improved efficacy than when given alone. Similarly, low and high dose combinations of ABT-239 (1 and 3 mg/kg) with TDZD-8 (5 and 10 mg/kg i.p.) produced greater neuroprotection than any other treatment group. Our findings suggests a neuroprotective potential of ABT-239 and its combinations with SVP and TDZD-8 against KA-induced neurotoxicity, possibly mediated through in part each by modulating Akt/GSK3ß and CREB pathways. The use of H3R antagonists as adjuvant in the treatment of human TLE might find potential utility, and can be pursued further.

Quantitative analysis of safranal in saffron extract and nanoparticle formulation by a validated high-performance thin-layer chromatographic method.

INTRODUCTION: Safranal is an effective anticonvulsant shown to act as an agonist at GABA(A) receptors. Nose to brain delivery via nanoparticle formulation might improve its brain delivery. A selective and sensitive analytical method is required for evaluation of safranal-based novel drug delivery systems. OBJECTIVE: To develop and validate a high-performance thin-layer chromatographic (HPTLC) method for the quantitative analysis of safranal as bulk, in saffron extract and in developed safranal-loaded nanoparticle formulation. METHODOLOGY: Chromatographic separation was achieved on silica gel pre-coated TLC aluminium plates 60F-254, using n-hexane:ethyl acetate (9 : 1, v/v) as the mobile phase. Quantitative analysis was carried out by densitometry at a wavelength of 310 nm. The method was validated and applied to detect related impurities, to analyse safranal in saffron extract and to evaluate safranal-loaded nanoparticles. RESULTS: Compact spots of safranal were observed at R(f) value 0.51 +/- 0.02. The method was linear (r = 0.9991) between 0.5 and 5.0 ng/spot. The intra- and inter-day precisions were 1.08-2.17 and 1. 86-3.47%, respectively. The limit of detection was 50 ng/spot and the limit of quantification was 150 ng/spot. The method proved to be accurate (recovery 97.4-102.0%) and was selective for safranal. Evaluation of safranal-loaded nanoparticle formulation demonstrated drug loading of 23.0%, encapsulation efficiency of 42.0% and sustained drug release following biphasic pattern. CONCLUSION: The present method is useful for the quantitative and qualitative analysis of safranal and safranal-loaded nanoparticle formulation. It provides significant advantages in terms of greater specificity and rapid analysis.