Amarendranath Choudhury

Neuroprotective Potential of Silymarin against CNS Disorders: Insight into the Pathways and Molecular Mechanisms of Action

Silymarin, a C25 containing flavonoid from the plant Silybum marianum, has been the gold standard drug to treat liver disorders associated with alcohol consumption, acute and chronic viral hepatitis, and toxin‐induced hepatic failures since its discovery in 1960. Apart from the hepatoprotective nature, which is mainly due to its antioxidant and tissue regenerative properties, Silymarin has recently been reported to be a putative neuroprotective agent against many neurologic diseases including Alzheimers and Parkinsons diseases, and cerebral ischemia. Although the underlying neuroprotective mechanism of Silymarin is believed to be due to its capacity to inhibit oxidative stress in the brain, it also confers additional advantages by influencing pathways such as β‐amyloid aggregation, inflammatory mechanisms, cellular apoptotic machinery, and estrogenic receptor mediation. In this review, we have elucidated the possible neuroprotective effects of Silymarin and the underlying molecular events, and suggested future courses of action for its acceptance as a CNS drug for the treatment of neurodegenerative diseases.

Cholesterol - A putative endogenous contributor towards Parkinson's disease.

Elevated levels of cholesterol and its metabolites (oxysterols) have been reported to be associated not only with several metabolic syndromes, but also become a prognostic risk factor of neurodegenerative diseases particularly Alzheimers disease. The incidence and the prospect of Alzheimers disease with respect to elevated levels of cholesterol have been studied extensively and reviewed earlier. Recently, several interesting findings have shown the occurrence of equivalent Parkinsonian pathologies in cellular neuronal models, mediated by oxysterols or excess exposure to cholesterol. In this regard, oxysterols are particular in causing alpha-synuclein aggregation and destruction of dopamine containing neurons in inxa0vitro models, which is linked to their direct influence on oxidative stress provoking potency. Inspite of the significant inxa0vitro reports, which suggest the relativeness of cholesterol or oxysterol towards Parkinsonism, several prospective clinical reports provided a negative or no correlation. However, few prospective clinical studies showed a positive correlation between plasma cholesterol and incidence of Parkinsons disease (PD). Also, few significant studies have convincingly demonstrated that high fat diet exacerbates parkinsonian pathologies, including loss of dopaminergic neurons and oxidative stress parameters in animal models of PD. The present review brings together all the neuropathological proceedings mediated by excess cholesterol or its metabolites in brain in the light of their contribution towards the onset of PD. Also we have reviewed the possibilities of cholesterol lowering efficacy of statin therapy, in reducing the occurrence of PD.

Cholesterol contributes to dopamine-neuronal loss in MPTP mouse model of Parkinson’s disease: Involvement of mitochondrial dysfunctions and oxidative stress

Hypercholesterolemia is a known contributor to the pathogenesis of Alzheimer’s disease while its role in the occurrence of Parkinson’s disease (PD) is only conjecture and far from conclusive. Altered antioxidant homeostasis and mitochondrial functions are the key mechanisms in loss of dopaminergic neurons in the substantia nigra (SN) region of the midbrain in PD. Hypercholesterolemia is reported to cause oxidative stress and mitochondrial dysfunctions in the cortex and hippocampus regions of the brain in rodents. However, the impact of hypercholesterolemia on the midbrain dopaminergic neurons in animal models of PD remains elusive. We tested the hypothesis that hypercholesterolemia in MPTP model of PD would potentiate dopaminergic neuron loss in SN by disrupting mitochondrial functions and antioxidant homeostasis. It is evident from the present study that hypercholesterolemia in naïve animals caused dopamine neuronal loss in SN with subsequent reduction in striatal dopamine levels producing motor impairment. Moreover, in the MPTP model of PD, hypercholesterolemia exacerbated MPTP-induced reduction of striatal dopamine as well as dopaminergic neurons in SN with motor behavioral depreciation. Activity of mitochondrial complexes, mainly complex-I and III, was impaired severely in the nigrostriatal pathway of hypercholesterolemic animals treated with MPTP. Hypercholesterolemia caused oxidative stress in the nigrostriatal pathway with increased generation of hydroxyl radicals and enhanced activity of antioxidant enzymes, which were further aggravated in the hypercholesterolemic mice with Parkinsonism. In conclusion, our findings provide evidence of increased vulnerability of the midbrain dopaminergic neurons in PD with hypercholesterolemia.

L-DOPA treatment in MPTP-mouse model of Parkinson’s disease potentiates homocysteine accumulation in substantia nigra

One of the intermediates of methionine cycle, the homocysteine (Hcy), elevates in plasma of Parkinsons disease (PD) patients undergoing L-DOPA (3,4-dihydroxyphenylalanine) therapy and has been regarded as a risk factor of the disease. Several evidences pointed out that Hcy causes degeneration of dopaminergic neurons. In rodent, elevated level of Hcy in brain or infusion of the same directly into the substantia nigra (SN) potentiates dopaminergic neurodegeneration. However, the influence of L-DOPA therapy on the levels of Hcy in dopamine-rich regions of the brain (striatum and SN) of experimental models of PD is not known. The present study, for the first time, tested the hypothesis that L-DOPA treatment in experimental mouse model of PD potentiates Hcy accumulation in the dopamine-rich regions of the brain. We found a significant elevation of Hcy level in nigrostriatum in naïve as well as parkinsonian mice as a result of chronic L-DOPA treatment. Interestingly, L-DOPA treatment significantly elevates Hcy level in nigra but not in striatum of parkinsonian mice, when compared with L-DOPA naïve group. However, there is no significant decrease in the number of dopaminergic neurons in SN region in the parkinsonian mice given L-DOPA treatment. Thus, the present study demonstrates that L-DOPA treatment potentiates the level of Hcy in the SN without causing aggravated neurodegeneration in parkinsonian mice model.

Cholesterol in Pancreatic β-Cell Death and Dysfunction: Underlying Mechanisms and Pathological Implications.

Abstract The mechanisms or causes of pancreatic &bgr;-cell death as well as impaired insulin secretion, which are the principal events of diabetic etiopathology, are largely unknown. Diabetic complications are known to be associated with abnormal plasma lipid profile, mainly elevated level of cholesterol and free fatty acids. However, in recent years, elevated plasma cholesterol has been implicated as a primary modulator of pancreatic &bgr;-cell functions as well as death. High-cholesterol diet in animal models or excess cholesterol in pancreatic &bgr;-cell causes transporter desensitization and results in morphometric changes in insulin granules. Moreover, cholesterol is also held responsible to cause oxidative stress, mitochondrial dysfunction, and activation of proapoptotic markers leading to &bgr;-cell death. The present review focuses on the pathways and molecularevents that occur in the &bgr;-cell under the influence of excess cholesterol that hampers the basal physiology of the cell leading to the progression of diabetes.

Hypercholesterolemia causes psychomotor abnormalities in mice and alterations in cortico-striatal biogenic amine neurotransmitters: Relevance to Parkinson's disease

&NA; The symptoms of Parkinsons disease (PD) include motor behavioral abnormalities, which appear as a result of the extensive loss of the striatal biogenic amine, dopamine. Various endogenous molecules, including cholesterol, have been put forward as putative contributors in the pathogenesis of PD. Earlier reports have provided a strong link between the elevated level of plasma cholesterol (hypercholesterolemia) and onset of PD. However, the role of hypercholesterolemia on brain functions in terms of neurotransmitter metabolism and associated behavioral manifestations remain elusive. We tested in Swiss albino mice whether hypercholesterolemia induced by high‐cholesterol diet would affect dopamine and serotonin metabolism in discrete brain regions that would precipitate in psychomotor behavioral manifestations. High‐cholesterol diet for 12 weeks caused a significant increase in blood total cholesterol level, which validated the model as hypercholesterolemic. Tests for akinesia, catalepsy, swimming ability and gait pattern (increased stride length) have revealed that hypercholesterolemic mice develop motor behavioral abnormalities, which are similar to the behavioral phenotypes of PD. Moreover, hypercholesterolemia caused depressive‐like behavior in mice, as indicated by the increased immobility time in the forced swim test. We found a significant depletion of dopamine in striatum and serotonin in cortex of hypercholesterolemic mice. The significant decrease in tyrosine hydroxylase immunoreactivity in striatum supports the observed depleted level dopamine in striatum, which is relevant to the pathophysiology of PD. In conclusion, hypercholesterolemia‐induced depleted levels of cortical and striatal biogenic amines reported hereby are similar to the PD pathology, which might be associated with the observed psychomotor behavioral abnormalities. HighlightsHypercholesterolemia in mice causes motor abnormalities and depression.Hypercholesterolemia causes cortico‐striatal serotonin and dopamine depletion.Hypercholesterolemia‐ a risk factor for Parkinsons disease.

Artificial Intelligence in Biological Data

Artificial Intelligence (AI) or Machine learning in present era serves as the primary choice for data mining and big data analysis. With effective learning and adaptation model, it provides solutions to several engineering applications. These include techniques such as Artificial Neural Network modelling, Reasoning based decision algorithms, Simulation models, DNA computing and Quantum computing among several others. With the application of AI in Biomedical research, the fuzziness and randomness in handling such type of data has significantly reduced. Rapid technological advancements have helped AI techniques evolve in manner which promotes handling such fuzzy data effectively and much more conveniently. The review presents a comprehensive view of machine learning and AI computing models, advanced data analytics and optimisation approaches used in Bioengineering such as Drug Designing and Analysis, Medical imaging, biologically inspired learning and adaption for analytics, etc.