ETHNOPHARMACOLOGICAL RELEVANCE:Withania somnifera (Family: Solanaceae), commonly known as Ashwagandha or Indian ginseng is distributed widely in India, Nepal, China and Yemen. The roots of plant consist of active phytoconstituents mainly withanolides, alkaloids and sitoindosides and are conventionally used for the treatment of multiple brain disorders.

AIM OF THE REVIEW:This review aims to critically assess and summarize the current state and implication of Ashwagandha in brain disorders. We have mainly focussed on the reported neuroactive phytoconstituents, available marketed products, pharmacological studies, mechanism of action and recent patents published related to neuroprotective effects of Ashwagandha in brain disorders.

MATERIALS AND METHODS:All the information and data was collected on Ashwagandha using keywords"Ashwagandha"along with"Phytoconstituents","Ayurvedic, Unani and Homeopathy marketed formulation","Brain disorders","Mechanism"and"Patents". Following sources were searched for data collection: electronic scientific databases such as Science Direct, Google Scholar, Elsevier, PubMed, Wiley On-line Library, Taylor and Francis, Springer; books such as AYUSH Pharmacopoeia; authentic textbooks and formularies.

RESULTS:Identified neuroprotective phytoconstituents of Ashwagandha are sitoindosides VII-X, withaferin A, withanosides IV, withanols, withanolide A, withanolide B, anaferine, beta-sitosterol, withanolide D with key pharmacological effects in brain disorders mainly anxiety, Alzheimer's, Parkinson's, Schizophrenia, Huntington's disease, dyslexia, depression, autism, addiction, amyotrophic lateral sclerosis, attention deficit hyperactivity disorder and bipolar disorders. The literature survey does not highlight any toxic effects of Ashwagandha. Further, multiple available marketed products and patents recognized its beneficial role in various brain disorders; however, very few data is available on mechanistic pathway and clinical studies of Ashwagandha for various brain disorders is scarce and not promising.

CONCLUSION:The review concludes the results of recent studies on Ashwagandha suggesting its extensive potential as neuroprotective in various brain disorders as supported by preclinical studies, clinical trials and published patents. However vague understanding of the mechanistic pathways involved in imparting the neuroprotective effect of Ashwagandha warrants further study to promote it as a promising drug candidate.

BACKGROUND:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no effective treatment. Stem cell therapy may be one of the promising treatment options for such patients.

AIM:To assess the feasibility, efficacy and safety of autologous bone marrow-derived stem cells in patients of ALS.

SETTINGS AND DESIGN:We conducted an open-label pilot study of autologous bone marrow-derived stem cells in patients with ALS attending the Neurology Clinic of a tertiary care referral centre.

MATERIALS AND METHODS:Ten patients with ALS with mean revised ALS Functional Rating Scale (ALSFRS-R) score of 30.2 (± 10.58) at baseline received intrathecal autologous bone marrow-derived stem cells. Primary end point was improvement in the ALSFRS-R score at 90, 180, 270 and 365 days post therapy. Secondary endpoints included ALSFRS-R subscores, time to 4-point deterioration, median survival and reported adverse events. Paired t-test was used to compare changes in ALSFRS-R from baseline and Kaplan-Meier analysis was used for survival calculations.

RESULTS:There was no significant deterioration in ALSFRS-R composite score from baseline at one-year follow-up (P=0.090). The median survival post procedure was 18.0 months and median time to 4-point deterioration was 16.7 months. No significant adverse events were reported.

CONCLUSION:Autologous bone marrow-derived stem cell therapy is safe and feasible in patients of ALS. Short-term follow-up of ALSFRS-R scores suggests a trend towards stabilization of disease. However, the benefit needs to be confirmed in the long-term follow-up period.

Curcumin is widely consumed in Asia either as turmeric directly or as one of the culinary ingredients in food recipes. The benefits of curcumin in different organ systems have been reported extensively in several neurological diseases and cancer. Curcumin has got its global recognition because of its strong antioxidant, anti-inflammatory, anti-cancer, and antimicrobial activities. Additionally, it is used in diabetes and arthritis as well as in hepatic, renal, and cardiovascular diseases. Recently, there is growing attention on usage of curcumin to prevent or delay the onset of neurodegenerative diseases. This review summarizes available data from several recent studies on curcumin in various neurological diseases such as Alzheimer's disease, Parkinson's disease, Multiple Sclerosis, Huntington's disease, Prions disease, stroke, Down's syndrome, autism, Amyotrophic lateral sclerosis, anxiety, depression, and aging. Recent advancements toward increasing the therapeutic efficacy of curcuma/curcumin formulation and the novel delivery strategies employed to overcome its minimal bioavailability and toxicity studies have also been discussed. This review also summarizes the ongoing clinical trials on curcumin for different neurodegenerative diseases and patent details of curcuma/curcumin in India.

Significant advances have increased our understanding of the molecular mechanisms of amyotrophic lateral sclerosis (ALS), yet this has not translated into any greatly effective therapies. It appears that a number of abnormal physiological processes occur simultaneously in this devastating disease. Ideally, a multidrug regimen, including glutamate antagonists, antioxidants, a centrally acting anti-inflammatory agent, microglial cell modulators (including tumor necrosis factor alpha [TNF-alpha] inhibitors), an antiapoptotic agent, 1 or more neurotrophic growth factors, and a mitochondrial function-enhancing agent would be required to comprehensively address the known pathophysiology of ALS. Remarkably, cannabis appears to have activity in all of those areas. Preclinical data indicate that cannabis has powerful antioxidative, anti-inflammatory, and neuroprotective effects. In the G93A-SOD1 ALS mouse, this has translated to prolonged neuronal cell survival, delayed onset, and slower progression of the disease. Cannabis also has properties applicable to symptom management of ALS, including analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. With respect to the treatment of ALS, from both a disease modifying and symptom management viewpoint, clinical trials with cannabis are the next logical step. Based on the currently available scientific data, it is reasonable to think that cannabis might significantly slow the progression of ALS, potentially extending life expectancy and substantially reducing the overall burden of the disease.

Coenzyme Q10 (CoQ10) is an essential cofactor of the electron transport gene as well as an important antioxidant, which is particularly effective within mitochondria. A number of prior studies have shown that it can exert efficacy in treating patients with known mitochondrial disorders. We investigated the potential usefulness of coenzyme Q10 in animal models of Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). It has been demonstrated that CoQ10 can protect against striatal lesions produced by the mitochondrial toxins malonate and 3-nitropropionic acid. These toxins have been utilized to model the striatal pathology, which occurs in HD. It also protects against 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice. CoQ10 significantly extended survival in a transgenic mouse model of ALS. CoQ10 can significantly extend survival, delay motor deficits and delay weight loss and attenuate the development of striatal atrophy in a transgenic mouse model of HD. In this mouse model, it showed additive efficacy when combined with the N-methyl-D-aspartate (NMDA) receptor antagonist, remacemide. CoQ10 is presently being studied as a potential treatment for early PD as well as in combination with remacemide as a potential treatment for HD.

Curcumin as a hydrophobic polyphenol is extracted from the rhizome of. Curcumin is widely used as a dietary spice and a topical medication for the treatment of inflammatory disorders in Asia. This compound also possesses remarkable anti-inflammatory and neuroprotective effects with the ability to pass from the blood brain barrier. Based on several pharmacological activities of curcumin, it has been introduced as an ideal candidate for different neurological disorders. Despite the pleiotropic activities of curcumin, poor solubility, rapid clearance and low stability have limited its clinical application. In recent years, nano-based drug delivery system has effectively improved the aqueous solubility and bioavailability of curcumin. In this review article, the effects of curcumin nanoparticles and their possible mechanism/s of action has been elucidated in various central nervous system (CNS)-related diseases including Parkinson's disease, Huntington disease, Alzheimer's disease, Multiple sclerosis, epilepsy and Amyotrophic Lateral Sclerosis. Furthermore, recent evidences about administration of nano-curcumin in the clinical trial phase have been described in the present review article.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) of nonmutant superoxide dismutase (SOD) type may be caused by toxicity of the reduced glutathione (GSH) precursors glutamate and cysteine, and sulfite (a metabolite of cysteine), which accumulate when one or more of the enzymes needed for GSH synthesis are defective. OBJECTIVES: A case is examined where the patient exhibited elevated sulfur on a hair mineral analysis, elevated blood cysteine, positive urine sulfite, elevated urine glutamate, and low whole blood GSH. During the time when strict dietary and supplement measures normalized the patient's whole blood GSH, blood cysteine, and urine sulfite, the patient did not experience additional physical decline. The possible causes of abnormalities of the patient's laboratory test results, as well as the nutrition measures used to normalize them, are discussed in relationship to the functions and importance of cysteine, sulfite, and glutamate in glutathione metabolism in ALS. CONCLUSIONS: Since elevated plasma cysteine has been reported in other ALS patients, sulfite and cysteine toxicity may be involved in other cases of ALS. Patients with ALS with nonmutant-SOD should be tested for sulfite toxicity, cysteine, glutamate and GSH levels, and whether they have low levels of GSH metabolism enzymes. Since glutamate metabolism appears to be inhibited by sulfite, research on the effect of sulfite on glutamate levels in patients with ALS should be pursued. Life might be prolonged in those patients with ALS with sulfite toxicity by closely monitoring the blood cysteine and urine sulfite levels and minimizing their dietary intake, as well as increasing GSH by using sublingual GSH. A long-term solution might be found through research to determine methods to increase GSH synthesis without using sulfur-containing supplements that may add to the cysteine and sulfite toxicity.

There is a continued need for therapies to improve respiratory function and quality of life in patients with amyotrophic lateral sclerosis. In this pilot trial, we studied 8 subjects with amyotrophic lateral sclerosis and respiratory involvement. We measured respiratory function and quality of life at baseline. We then taught subjects diaphragm training, a method of breath control designed to improve respiratory muscle strength and efficiency. We repeated measures of respiratory function and quality of life 6 and 12 weeks later. There was no significant improvement in any outcome measure after instituting diaphragm training. There was a nonsignificant trend toward a slower rate of decline in respiratory function in those subjects who mastered the technique; however, only half the subjects were able to successfully change their pattern of breathing. A larger study of this technique is warranted; however, in determining the sample size for a larger study, the difficulty for patients in mastering the technique must be taken into consideration.

Since its introduction in 1921, the ketogenic diet has been in continuous use for children with difficult-to-control epilepsy. After decades of relative disuse, it is now both extremely popular and well studied, with approximately two-thirds of children demonstrating significant seizure reduction after 6 months. It is being used for less intractable seizures in children as well as recently adults. Modifications that help improve tolerability include the medium chain triglyceride diet, modified Atkins diet, and low glycemic index treatment. Major side effects include acidosis, increased cholesterol, kidney stones, gastroesophageal reflux, and growth disturbance. However, these side effects are usually treatable and nowadays often even preventable. Future non-epilepsy indications such as Alzheimer disease, amyotrophic lateral sclerosis, autism, and brain tumors are under active investigation. This dietary treatment for epilepsy has undergone a rebirth. Its widespread use in Poland and Europe is a welcome additional treatment for those with drug-resistant epilepsy.

Amyotrophic lateral sclerosis (ALS) is a paralyzing disorder that is characterized by the progressive degeneration and death of motor neurons. Acupuncture or electroacupuncture (EA) has been used for the treatment of various conditions including osteoarthritis, asthma, and other types of chronic pain conditions. It has been hypothesized that acupuncture exerts anti-inflammatory and anti-nociceptive effects on inflammatory reactions processes. The purpose of this study was to determine whether acupuncture at a specific acupoint could produce anti-inflammatory responses and suppress motor neuron loss in the hG93ASOD1 mouse, commonly used as a model for inherited ALS. We delivered EA at the Zusanli (ST36) acupuncture point in the symptomatic hSOD1G93A animal model. The EA-treated mutant hSOD1 transgenic mice showed decreases in microglial cell activity and TNF-alpha expression in the spinal cord and brain stem. Furthermore, EA significantly improved motor activity compared to the control group and reduced neuronal cell loss in hSOD1G93A mice. Our research suggests a potential functional link between EA therapy and anti-neuroinflammatory response in an ALS animal model.

Existential well-being (EWB) and spirituality issues are important factors in determining quality of life (QoL) in amyotrophic lateral sclerosis (ALS) patients. No conclusive data among the relation between patient's EWB, their spirituality and caregivers' QoL are available. In the mainframe of a longitudinal study, we performed a cross-sectional analysis aimed to investigate EWB and spirituality issues in sporadic ALS (SALS) patients and the relations with caregivers' psychological features. Thirty-seven SALS patients, together with their caregivers, consecutively recruited at NEuroMuscular Omnicentre, in Milan, were included in this study. EWB and spirituality questions were administrated to patients and caregivers. Caregivers also completed questionnaires about quality of life (MQoL-SI), care burden (ZBI), depression (BDI) and anxiety (STAI). Both EWBs and questions about spirituality of SALS patients showed a positive correlation with MQoL-SI and EWBs in their caregivers. Conversely, SALS patients' EWB and spirituality were negatively correlated with caregivers' STAI, BDI and ZBI scores. In conclusion, existential well-being, as well as spirituality issues, perceived by SALS patients seems to be directly related with quality of life, severity of mood disturbance and burden experienced by their caregivers.

The activity of glutathione peroxidase (GSH-Px) as well as the activities of other antioxidative enzymes: CuZn superoxide dismutase (CuZn SOD), catalase (CAT), glutathione reductase (GR) in erythrocytes, as well as the activity of plasma glutathione transferase (GST), and the plasma content of vitamins E and C were evaluated in 35 sporadic amyotrophic lateral sclerosis (sALS) patients. The results revealed significantly decreased activity of both GSH-Px and CuZn SOD in sALS patients compared with the control. These data showed that a disturbed oxidative/antioxidative balance in sALS patients exists not only in motoneurons but also in the blood. The effect of exogenously administered selenium (Se), antioxidants, amino acids, a Ca2+ channel blocker such as nimodipine, and their combination in Alsamin was evaluated by screening parameter levels after 9 weeks of treatment. Only the use of all components together enhanced the activity of GSH-Px and the amount of vitamin E in sALS patients. Judging by the results of clinical trials, this treatment slowed the course of the disease.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease. Epidemiologic data suggest that malnutrition is a common feature in amyotrophic lateral sclerosis and being overweight or obese confers a survival advantage in this patient population. In amyotrophic lateral sclerosis mouse models, a high-fat diet has been shown to lead to weight gain and prolonged survival. However, little research has been conducted to test whether nutritional interventions might ameliorate the disease course in humans. Here we review the currently available evidence supporting the potential role of dietary interventions as a therapeutic tool for amyotrophic lateral sclerosis. Ultimately, determining whether a high-fat or ketogenic diet could be beneficial in amyotrophic lateral sclerosis will require large randomized, placebo-controlled clinical trials.

RATIONALE:Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease causing paralysis and death from respiratory failure. Strategies to preserve and/or restore respiratory function are critical for successful treatment. Although breathing capacity is maintained until late in disease progression in rodent models of familial ALS (SOD1(G93A) rats and mice), reduced numbers of phrenic motor neurons and decreased phrenic nerve activity are observed. Decreased phrenic motor output suggests imminent respiratory failure.

OBJECTIVES:To preserve or restore phrenic nerve activity in SOD1(G93A) rats at disease end stage.

METHODS:SOD1(G93A) rats were injected with human neural progenitor cells (hNPCs) bracketing the phrenic motor nucleus before disease onset, or exposed to acute intermittent hypoxia (AIH) at disease end stage.

MEASUREMENTS AND MAIN RESULTS:The capacity to generate phrenic motor output in anesthetized rats at disease end stage was: (1) transiently restored by a single presentation of AIH; and (2) preserved ipsilateral to hNPC transplants made before disease onset. hNPC transplants improved ipsilateral phrenic motor neuron survival.

CONCLUSIONS:AIH-induced respiratory plasticity and stem cell therapy have complementary translational potential to treat breathing deficits in patients with ALS.

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Marijuana has been proposed as treatment for a widening spectrum of medical conditions. Marijuana is a substance with many properties that may be applicable to the management of amyotrophic lateral sclerosis (ALS). These include analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. In addition, marijuana has now been shown to have strong antioxidative and neuroprotective effects, which may prolong neuronal cell survival. In areas where it is legal to do so, marijuana should be considered in the pharmacological management of ALS. Further investigation into the usefulness of marijuana in this setting is warranted.

BACKGROUND AND PURPOSE:Studies investigating psychological interventions for the promotion of well-being in people with amyotrophic lateral sclerosis (ALS) are lacking. The purpose of the current study was to examine the use of an ALS-specific mindfulness-based intervention for improving quality of life in this population.

METHODS:A randomized, open-label and controlled clinical trial was conducted on the efficacy of an ALS-specific meditation programme in promoting quality of life. Adults who received a diagnosis of ALS within 18 months were randomly assigned either to usual care or to an 8-week meditation training based on the original mindfulness-based stress reduction programme and tailored for people with ALS. Quality of life, assessed with the ALS-Specific Quality of Life Revised scale, represented the primary outcome, whilst secondary outcomes included anxiety and depression, assessed with the Hospital Anxiety and Depression Scale, and specific quality of life domains. Participants were assessed at recruitment and after 2, 6 and 12 months. The efficacy of the treatment was assessed on an intention-to-treat basis of a linear mixed model.

RESULTS:A hundred participants were recruited between November 2012 and December 2014. Over time, there was a significant difference between the two groups in terms of quality of life (β = 0.24, P = 0.015, d = 0.89). Significant differences between groups over time were also found for anxiety, depression, negative emotions, and interaction with people and the environment.

CONCLUSIONS:An ALS-specific meditation programme is beneficial for the quality of life and psychological well-being of people with ALS.

BACKGROUND:The aging process is not univocal, both body and brain age. Neurological disorders are a major cause of disability and death worldwide. According to the Global Burden of Disease Study 2015, neurological diseases are the second most common cause of death and 16.8% of total deaths are caused by neurological diseases worldwide. Neurological disease deaths have risen 36% worldwide in 25 years. Melatonin is a neuroregulator hormone that has free radical scavenger, strong antioxidant, anti-inflammatory, and immunosuppressive actions. These major properties of melatonin can play an important role in the pathophysiological mechanisms of neurological diseases. In addition, melatonin is necessary for circadian rhythm. Studies have shown that melatonin levels are low in people with neurological diseases. Both preventive and therapeutic effects of melatonin are known for many diseases, including neurological diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, epilepsy, headache, etc.). Based on all these reasons, clinical trials of melatonin were performed and successful results were declared.

CONCLUSIONS:In this review, biological and chemical knowledge of melatonin, its experimental effects, and the clinical impact on patients with neurological disorders were described. According to all of the beneficial results obtained from experimental and clinical trials, melatonin may have a prophylactic and therapeutic effect on neurological diseases. Strong collaboration between neurologists and health service policy makers is needed to encourage use of melatonin in the patients suffering from neurological diseases. Melatonin may be the solution we have been looking for.

Mitochondria play a central role in the cell physiology. Besides their classic function of energy metabolism, mitochondria are involved in multiple cell functions including energy distribution through the cell, energy/heat modulation, regulation of reactive oxygen species (ROS), calcium homeostasis and apoptosis control. Simultaneously mitochondria are the main producer and target of ROS and with the result, multiple mitochondrial diseases are related to ROS induced mitochondrial injuries. Increased free radical generation, enhanced mitochondrial inducible nitric oxide (NO) synthase activity, enhanced NO production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pore all have been suggested as factors responsible for impaired mitochondrial function. Among these, neurodegenerative diseases such as Alzheimer´s disease (AD), Parkinson´s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington´s disease (HD) and aging are caused by ROS-induced mitochondrial dysfunctions. Melatonin, the major hormone of the pineal gland, also acts as an antioxidant and as a regulator of mitochondrial bioenergeticfunction. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other antioxidants, and thus has emerged as a major potential therapeutic tool for treating neurodegenerative disorders. Multiple in vitro and in vivo experiments have shown the protective role of melatonin for preventing oxidative stress induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. Keeping these functions into consideration, this article was framed to review the protective role of melatonin with mechanistic insights against mitochondrial diseases, and may suggest the new avenues for safe and effective treatment modalities against these devastating neurodegenerative diseases. Future insights have also been discussed.