Current Neuropharmacology - Volume 14, Issue 6, 2016

Gliomas are the most common primary brain tumors either benign or malignant originating from the glial tissue. Glioblastoma multiforme (GBM) is the most prevalent and aggressive form among all gliomas, associated with decimal prognosis due to it's high invasive nature. GBM is also characterized by high recurrence rate and apoptosis resistance features which make the therapeutic targeting very challenging. Mitochondria are key cellular organelles that are acting as focal points in diverse array of cellular functions such as cellular energy metabolism, regulation of ion homeostasis, redox signaling and cell death. Eventual findings of mitochondrial dysfunction include preference of glycolysis over oxidative phosphorylation, enhanced reactive oxygen species generation and abnormal mitochondria mediated apoptotic machinery are frequently observed in various malignancies including gliomas. In particular, gliomas harbor mitochondrial structure abnormalities, genomic mutations in mtDNA, altered energy metabolism (Warburg effect) along with mutations in isocitrate dehydrogenase (IDH) enzyme. Numerous natural compounds have shown efficacy in the treatment of gliomas by targeting mitochondrial aberrant signaling cascades. Some of the natural compounds directly target the components of mitochondria whereas others act indirectly through modulating metabolic abnormalities that are consequence of the mitochondrial dysfunction. The present review offers a molecular insight into mitochondrial pathology in gliomas and therapeutic mechanisms of some of the promising natural compounds that target mitochondrial dysfunction. This review also sheds light on the challenges and possible ways to overcome the hurdles associated with these natural compounds to enter into the clinical market.

Parkinson’s disease (PD) is a movement disorder and is associated with some of the intellectual disabilities like cognitive dysfunctions. PD associated cognitive dysfunctions have been proved well in both preclinical and clinical set ups. Like other neurodegenerative diseases, insults to mitochondria have a significant role in the pathobiology of PD associated dementia (PDD). Neurotoxins like MPTP, mutations of the mitochondrial genes, oxidative stress, imbalanced redox mechanisms and dysregulated mitochondrial dynamics have been implicated in mitochondrial dysfunctions and have paramount importance in the pathobiology of PDD. However, the extent of contribution of mitochondrial dysfunctions towards cognitive deficits in PD has not been characterized completely. In this review we highlight on the contribution of mitochondrial dysfunction to PDD. We also highlight different behavioural tests used in nonhuman primate and rodent models for assessing cognitive deficits and some common techniques for evaluation of mitochondrial dysfunction in PDD.

Background: Peripheral neuropathies are a group of diseases characterized by malfunctioning of peripheral nervous system. Neuropathic pain, one of the core manifestations of peripheral neuropathy remains as the most severe disabling condition affecting the social and daily routine life of patients suffering from peripheral neuropathy. Method: The current review is aimed at unfolding the possible role of mitochondrial dysfunction in peripheral nerve damage and to discuss on the probable therapeutic strategies against neuronal mitotoxicity. The article also highlights the therapeutic significance of maintaining a healthy mitochondrial environment in neuronal cells via pharmacological management in context of peripheral neuropathies. Results: Aberrant cellular signaling coupled with changes in neurotransmission, peripheral and central sensitization are found to be responsible for the pathogenesis of variant toxic neuropathies. Current research reports have indicated the possible involvement of mitochondria mediated redox imbalance as one of the principal causes of neuropathy aetiologies. In addition to imbalance in redox homeostasis, mitochondrial dysfunction is also responsible for alterations in physiological bioenergetic metabolism, apoptosis and autophagy pathways. Conclusions: In spite of various etiological factors, mitochondrial dysfunction has been found to be a major pathomechanism underlying the neuronal dysfunction associated with peripheral neuropathies. Pharmacological modulation of mitochondria either directly or indirectly is expected to yield therapeutic relief from various primary and secondary mitochondrial diseases.

Background: Depression is the most debilitating neuropsychiatric disorder with significant impact on socio-occupational and well being of individual. The exact pathophysiology of depression is still enigmatic though various theories have been put forwarded. There are evidences showing that mitochondrial dysfunction in various brain regions is associated with depression. Recent findings have sparked renewed appreciation for the role of mitochondria in many intracellular processes coupled to synaptic plasticity and cellular resilience. New insights in depression pathophysiology are revolving around the impairment of neuroplasticity. Mitochondria have potential role in ATP production, intracellular Ca²⁺ signalling to establish membrane stability, reactive oxygen species (ROS) balance and to execute the complex processes of neurotransmission and plasticity. So understanding the various concepts of mitochondrial dysfunction in pathogenesis of depression indubitably helps to generate novel and more targeted therapeutic approaches for depression treatment. Objective: The review was aimed to give a comprehensive insight on role of mitochondrial dysfunction in depression. Result: Targeting mitochondrial dysfunction and enhancing the mitochondrial functions might act as potential target for the treatment of depression. Conclusion: Literature cited in this review highly supports the role of mitochondrial dysfunction in depression. As impairment in the mitochondrial functions lead to the generation of various insults that exaggerate the pathogenesis of depression. So, it is useful to study mitochondrial dysfunction in relation to mood disorders, synaptic plasticity, neurogenesis and enhancing the functions of mitochondria might show promiscuous effects in the treatment of depressed patients.

Background: Neurogenesis is most active during pre-natal development, however, it persists throughout the human lifespan. The putative role of mitochondria in neurogenesis and angiogenesis is gaining importance. Since, ETB receptor mediated neurogenesis and angiogenesis has been identified, the role of these receptors with relevance to mitochondrial functions is of interest. Methods: In addition to work from our laboratory, we undertook an extensive search of bibliographic databases for peer-reviewed research literature. Specific technical terms such as endothelin, mitochondria and neurogenesis were used to seek out and critically evaluate literature that was relevant. Results: The ET family consists of three isopeptides (ET-1, ET-2 and ET-3) that produce biological actions by acting on two types of receptors (ETA and ETB). In the central nervous system (CNS) ETA receptors are potent constrictors of the cerebral vasculature and appear to contribute in the causation of cerebral ischemia. ETA receptor antagonists have been found to be effective in animal model of cerebral ischemia; however, clinical studies have shown no efficacy. Mitochondrial functions are critically important for several neural development processes such as neurogenesis, axonal and dendritic growth, and synaptic formation. ET appears to impair mitochondrial functions through activation of ETA receptors. On the other hand, blocking ETB receptors has been shown to trigger apoptotic processes by activating intrinsic mitochondrial pathway. Mitochondria are important for their role in molecular regulation of neurogenesis and angiogenesis. Stimulation of ETB receptors in the adult ischemic brain has been found to promote angiogenesis and neurogenesis mediated through vascular endothelial growth factor and nerve growth factor. It will be interesting to investigate the effect of ETB receptor stimulation on mitochondrial functions in the CNS following cerebral ischemia. Conclusion: The findings of this review implicate brain ETB receptors in angiogenesis and neurogenesis following cerebral ischemia, it is possible that the positive effect of stimulating ETB receptors in cerebral ischemia may be mediated through mitochondrial functions.

The mechanisms underlying neurodegenerative disorders are complex and multifactorial; however, accumulating evidences suggest few common shared pathways. These common pathways include mitochondrial dysfunction, intracellular Ca²⁺ overload, oxidative stress and inflammation. Often multiple pathways co-exist, and therefore limit the benefits of therapeutic interventions. Nutraceuticals have recently gained importance owing to their multifaceted effects. These food-based approaches are believed to target multiple pathways in a slow but more physiological manner without causing severe adverse effects. Available information strongly supports the notion that apart from preventing the onset of neuronal damage, nutraceuticals can potentially attenuate the continued progression of neuronal destruction. In this article, we i) review the common pathways involved in the pathogenesis of the toxicants-induced neurotoxicity and neurodegenerative disorders with special emphasis on Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Multiple sclerosis (MS) and Amyotrophic lateral sclerosis (ALS), and ii) summarize current research advancements on the effects of nutraceuticals against these detrimental pathways.

In recent years there has been a growing body of clinical and laboratory evidence demonstrating the neuroprotective effects of estrogen and progesterone after traumatic brain injury (TBI) and spinal cord injury (SCI). In humans, women have been shown to have a lower incidence of morbidity and mortality after TBI compared with age-matched men. Similarly, numerous laboratory studies have demonstrated that estrogen and progesterone administration is associated with a mortality reduction, improvement in neurological outcomes, and a reduction in neuronal apoptosis after TBI and SCI. Here, we review the evidence that supports hormone-related neuroprotection and discuss possible underlying mechanisms. Estrogen and progesterone-mediated neuroprotection are thought to be related to their effects on hormone receptors, signaling systems, direct antioxidant effects, effects on astrocytes and microglia, modulation of the inflammatory response, effects on cerebral blood flow and metabolism, and effects on mediating glutamate excitotoxicity. Future laboratory research is needed to better determine the mechanisms underlying the hormones’ neuroprotective effects, which will allow for more clinical studies. Furthermore, large randomized clinical control trials are needed to better assess their role in human neurodegenerative conditions.

Neuromodulation, including invasive and non-invasive stimulation, has been used to treat intractable chronic pain. However, the mechanisms by which neuromodulation produces antinociceptive effect still remain uncertain. Optogenetic manipulation, a recently developed novel approach, has already proven its value to clinicians by providing new insights into mechanisms of current clinical neuromodulation methods as well as pathophysiology of nervous system diseases at the circuit level. Here, we discuss the principles of two neuromodulation methods (deep brain stimulation and motor cortex stimulation) and their applications in pain treatment. More important, we summarize the new information from recent studies regarding optogenetic manipulation in neuroscience research and its potential utility in pain study.