Sandeep Vasant More

Cellular and Molecular Mediators of Neuroinflammation in the Pathogenesis of Parkinson’s Disease

Neuroinflammation is a host-defense mechanism associated with restoration of normal structure and function of the brain and neutralization of an insult. Increasing neuropathological and biochemical evidence from the brains of individuals with Parkinsons disease (PD) provides strong evidence for activation of neuroinflammatory pathways. Microglia, the resident innate immune cells, may play a major role in the inflammatory process of the diseased brain of patients with PD. Although microglia forms the first line of defense for the neural parenchyma, uncontrolled activation of microglia may directly affect neurons by releasing various molecular mediators such as inflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-6, and IL-1β), nitric oxide, prostaglandin E2, and reactive oxygen and nitrogen species. Moreover, recent studies have reported that activated microglia phagocytose not only damaged cell debris but also intact neighboring cells. This phenomenon further supports their active participation in self-enduring neuronal damage cycles. As the relationship between PD and neuroinflammation is being studied, there is a realization that both cellular and molecular mediators are most likely assisting pathological processes leading to disease progression. Here, we discuss mediators of neuroinflammation, which are known activators released from damaged parenchyma of the brain and result in neuronal degeneration in patients with PD.

The role of free radicals in the aging brain and Parkinson's Disease: convergence and parallelism.

Free radical production and their targeted action on biomolecules have roles in aging and age-related disorders such as Parkinson’s disease (PD). There is an age-associated increase in oxidative damage to the brain, and aging is considered a risk factor for PD. Dopaminergic neurons show linear fallout of 5–10% per decade with aging; however, the rate and intensity of neuronal loss in patients with PD is more marked than that of aging. Here, we enumerate the common link between aging and PD at the cellular level with special reference to oxidative damage caused by free radicals. Oxidative damage includes mitochondrial dysfunction, dopamine auto-oxidation, α-synuclein aggregation, glial cell activation, alterations in calcium signaling, and excess free iron. Moreover, neurons encounter more oxidative stress as a counteracting mechanism with advancing age does not function properly. Alterations in transcriptional activity of various pathways, including nuclear factor erythroid 2-related factor 2, glycogen synthase kinase 3β, mitogen activated protein kinase, nuclear factor kappa B, and reduced activity of superoxide dismutase, catalase and glutathione with aging might be correlated with the increased incidence of PD.

Gastrodin Protects Apoptotic Dopaminergic Neurons in a Toxin-Induced Parkinson’s Disease Model

Gastrodia elata (GE) Blume is one of the most important traditional plants in Oriental countries and has been used for centuries to improve various conditions. The phenolic glucoside gastrodin is an active constituent of GE. The aim of this study was to investigate the neuroprotective role of gastrodin in 1-methyl-4-phenylpyridinium (MPP+)/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP) induced human dopaminergic SH-SY5Y cells and mouse model of Parkinsons disease (PD), respectively. Gastrodin significantly and dose dependently protected dopaminergic neurons against neurotoxicity through regulating free radicals, Bax/Bcl-2 mRNA, caspase-3, and cleaved poly(ADP-ribose) polymerase (PARP) in SH-SY5Y cells stressed with MPP+. Gastrodin also showed neuroprotective effects in the subchronic MPTP mouse PD model by ameliorating bradykinesia and motor impairment in the pole and rotarod tests, respectively. Consistent with this finding, gastrodin prevented dopamine depletion and reduced reactive astrogliosis caused by MPTP as assessed by immunohistochemistry and immunoblotting in the substantiae nigrae and striatata of mice. Moreover, gastrodin was also effective in preventing neuronal apoptosis by attenuating antioxidant and antiapoptotic activities in these brain areas. These results strongly suggest that gastrodin has protective effects in experimental PD models and that it may be developed as a clinical candidate to ameliorate PD symptoms.

The Role of Bioactive Compounds on the Promotion of Neurite Outgrowth

Neurite loss is one of the cardinal features of neuronal injury. Apart from neuroprotection, reorganization of the lost neuronal network in the injured brain is necessary for the restoration of normal physiological functions. Neuritogenic activity of endogenous molecules in the brain such as nerve growth factor is well documented and supported by scientific studies which show innumerable compounds having neurite outgrowth activity from natural sources. Since the damaged brain lacks the reconstructive capacity, more efforts in research are focused on the identification of compounds that promote the reformation of neuronal networks. An abundancy of natural resources along with the corresponding activity profiles have shown promising results in the field of neuroscience. Recently, importance has also been placed on understanding neurite formation by natural products in relation to neuronal injury. Arrays of natural herbal products having plentiful active constituents have been found to enhance neurite outgrowth. They act synergistically with neurotrophic factors to promote neuritogenesis in the diseased brain. Therefore use of natural products for neuroregeneration provides new insights in drug development for treating neuronal injury. In this study, various compounds from natural sources with potential neurite outgrowth activity are reviewed in experimental models.

Nuclear factor erythroid 2-related factor 2 signaling in Parkinson disease: a promising multi therapeutic target against oxidative stress, neuroinflammation and cell death.

Parkinsons disease (PD) is the second most common progressive neurodegenerative disorder with increased oxidative stress as central component. Till date, treatments related to PD are based on restoring dopamine either by targeting neurotransmitter and/or at receptor levels. These therapeutic approaches try to repair damage but do not address the underlying processes such as oxidative stress and neuroinflammation that contribute to cell death. The central nervous system maintains a robust antioxidant defense mechanism consisting of several cytoprotective genes and enzymes whose expression is controlled by antioxidant response element (ARE) which further depends on activation of nuclear factor erythroid 2-related factor 2 (Nrf2). In response to oxidative or electrophilic stress transcription factor Nrf2 binds to ARE and rescues the cells from oxidative stress and neuroinflammation. Recently, Nrf2 has been utilized as a drug target and some agents are currently under clinical trial. Owing to the potential role of Nrf2 in counteracting oxidative stress and neuroinflammation seen in PD, here we have focused on the molecular mechanism of the Nrf2/ARE antioxidant defense pathway in PD. Further, we also summarize published reports on the potential inducers of Nrf2 that demonstrate neuroprotective effects in experimental models of PD with possible future strategies to increase the transcriptional level of Nrf2 as a therapeutic strategy to provide neuroprotection of damaged dopaminergic neurons in PD.

Promising cannabinoid-based therapies for Parkinson's disease: motor symptoms to neuroprotection

Parkinson’s disease (PD) is a slow insidious neurological disorder characterized by a loss of dopaminergic neurons in the midbrain. Although several recent preclinical advances have proposed to treat PD, there is hardly any clinically proved new therapeutic for its cure. Increasing evidence suggests a prominent modulatory function of the cannabinoid signaling system in the basal ganglia. Hence, use of cannabinoids as a new therapeutic target has been recommended as a promising therapy for PD. The elements of the endocannabinoid system are highly expressed in the neural circuit of basal ganglia wherein they bidirectionally interact with dopaminergic, glutamatergic, and GABAergic signaling systems. As the cannabinoid signaling system undergoes a biphasic pattern of change during progression of PD, it explains the motor inhibition typically observed in patients with PD. Cannabinoid agonists such as WIN-55,212-2 have been demonstrated experimentally as neuroprotective agents in PD, with respect to their ability to suppress excitotoxicity, glial activation, and oxidative injury that causes degeneration of dopaminergic neurons. Additional benefits provided by cannabinoid related compounds including CE-178253, oleoylethanolamide, nabilone and HU-210 have been reported to possess efficacy against bradykinesia and levodopa-induced dyskinesia in PD. Despite promising preclinical studies for PD, use of cannabinoids has not been studied extensively at the clinical level. In this review, we reassess the existing evidence suggesting involvement of the endocannabinoid system in the cause, symptomatology, and treatment of PD. We will try to identify future threads of research that will help in the understanding of the potential therapeutic benefits of the cannabinoid system for treating PD.

Promising Therapeutics with Natural Bioactive Compounds for Improving Learning and Memory — A Review of Randomized Trials

Cognitive disorders can be associated with brain trauma, neurodegenerative disease or as a part of physiological aging. Aging in humans is generally associated with deterioration of cognitive performance and, in particular, learning and memory. Different therapeutic approaches are available to treat cognitive impairment during physiological aging and neurodegenerative or psychiatric disorders. Traditional herbal medicine and numerous plants, either directly as supplements or indirectly in the form of food, improve brain functions including memory and attention. More than a hundred herbal medicinal plants have been traditionally used for learning and memory improvement, but only a few have been tested in randomized clinical trials. Here, we will enumerate those medicinal plants that show positive effects on various cognitive functions in learning and memory clinical trials. Moreover, besides natural products that show promising effects in clinical trials, we briefly discuss medicinal plants that have promising experimental data or initial clinical data and might have potential to reach a clinical trial in the near future.

Recent Advances on the Neuroprotective Potential of Antioxidants in Experimental Models of Parkinson’s Disease

Parkinson’s disease (PD), a neurodegenerative movement disorder of the central nervous system (CNS) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain. Although the etiology of PD is not completely understood and is believed to be multifactorial, oxidative stress and mitochondrial dysfunction are widely considered major consequences, which provide important clues to the disease mechanisms. Studies have explored the role of free radicals and oxidative stress that contributes to the cascade of events leading to dopamine cell degeneration in PD. In general, in-built protective mechanisms consisting of enzymatic and non-enzymatic antioxidants in the CNS play decisive roles in preventing neuronal cell loss due to free radicals. But the ability to produce these antioxidants decreases with aging. Therefore, antioxidant therapy alone or in combination with current treatment methods may represent an attractive strategy for treating or preventing the neurodegeneration seen in PD. Here we summarize the recent discoveries of potential antioxidant compounds for modulating free radical mediated oxidative stress leading to neurotoxicity in PD.

Recent updates in redox regulation and free radical scavenging effects by herbal products in experimental models of Parkinson's disease.

Parkinson’s disease (PD) is a complex multifactorial disease marked by extensive neuropathology in the brain with selective yet prominent and progressive loss of mid-brain dopaminergic neurons. The etiological factors involved in the development of PD are still elusive, but oxidative stress arising when reactive oxygen species (ROS) exceed amounts required for normal redox signaling is considered one of the major factors. ROS cause oxidative damage to proteins, lipids, and DNA and are one of the most prominent factors related to neurodegeneration. Pre-clinical and clinical studies clearly demonstrate the effectiveness of oxidative stress in the pathogenesis of PD. Therefore, regulation of redox signaling and inhibiting excess ROS would contribute greatly not only to extend longevity but also to ameliorate the progression of dopaminergic cell death seen in patients with PD. Several herbal products are beneficial for maintaining nerve cell function and for treating various neurodegenerative disorders by reducing oxidative stress. Here, we summarize the recent knowledge concerning promising herbs that have shown significant beneficial effects based on regulation of redox status and ROS inhibition in toxin-induced PD models.

Advances in neuroprotective ingredients of medicinal herbs by using cellular and animal models of Parkinson's disease.

Parkinsons disease (PD) is a multifactorial disorder, which is neuropathologically identified by age-dependent neurodegeneration of dopaminergic neurons in the substantia nigra. Development of symptomatic treatments has been partly successful for PD research, but there remain a number of inadequacies in therapeutic strategies for the disease. The pathogenesis of PD remains intricate, and the present anti-PD treatments appears to be clinically insufficient. Comprehensive research on discovery of novel drug candidates has demonstrated that natural products, such as medicinal herbs, plant extracts, and their secondary metabolites, have great potential as therapeutics with neuroprotective activity in PD. Recent preclinical studies suggest that a number of herbal medicines and their bioactive ingredients can be developed into optimum pharmaceuticals for treating PD. In many countries, traditional herbal medicines are used to prevent or treat neurodegenerative disorders, and some have been developed as nutraceuticals or functional foods. Here we focus on recent advances of the evidence-linked neuroprotective activity of bioactive ingredients of herbal origin in cellular and animal models of PD research.