CNS & neurological disorders drug targets
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CNS Neurol Disord Drug Targets · Jan 2014
Targeting of peripherally expressed pain-related molecules in injury- induced chronic neuropathic pain.
Neuropathic pain is a chronic disability associated with a dysfunction of the nervous system, initiated by a primary lesion or disease. Even after resolution of the initiating pathology, neuropathic pain often persists, leading to a significantly diminished quality of life. A vast literature has documented alterations in the expression and distribution of various pain-related proteins in the peripheral nervous system following injury or disease. ⋯ A key advantage of therapy directed peripherally is that penetration of the therapeutic into the CNS is not entirely necessary, thereby reducing the risk of adverse psychomotor effects. While a number of fascinating targets have been identified in preclinical rodent models, there is a need to confirm that they are in fact relevant to clinical neuropathic pain. Thus, the current review will also discuss the extent to which clinical data confirms the findings of preclinical studies.
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CNS Neurol Disord Drug Targets · Jan 2014
ReviewGut emotions - mechanisms of action of probiotics as novel therapeutic targets for depression and anxiety disorders.
A priority clinical and research agenda in mood and anxiety disorders is to identify determinants that influence illness trajectory and outcome. Over the past decade, studies have demonstrated a bidirectional relationship between the gut microbiome and brain function (i.e., the microbiota-gut-brain axis). Probiotic treatments and developmental analysis of the microbiome may provide potential treatments and preventative measures for depressive and anxiety disorders. ⋯ Notwithstanding some inconsistencies and methodological limitations across trials, clinical studies suggest that probiotics may mitigate anxiety symptoms. However, future studies should investigate the anxiolytic and antidepressant effects of probiotics in more phenotypically homogeneous populations. In conclusion, the emerging concept of a gut microbiota-brain axis suggests that the modulation of the gut microbiota may provide a novel therapeutic target for the treatment and/or prevention of mood and anxiety disorders.
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CNS Neurol Disord Drug Targets · Jan 2014
ReviewNovel approach to the role of NMDA receptors in traumatic brain injury.
For more than two decades the intensive research effort on the role of NMDA receptors (NMDAR) in traumatic brain injury (TBI) and cerebral ischemia (stroke) was led by the observations that extracellular concentrations of glutamate and aspartate are elevated after the insult and play a major role in brain pathologies. Indeed, NMDAR antagonists were shown to improve post-injury recovery in animal models and subsequently, large scale placebo-controlled clinical trials in TBI and stroke were performed with NMDAR antagonists. However, all these trials have demonstrated either no benefit or even deleterious effects. ⋯ Experiments to optimize the DCS treatment paradigm showed that similar benefits were demonstrated in TBI mice whether the drug was given as a single injection at 24 or 72 hrs post injury, or as double (24 and 48 hrs) or triple (24, 48 and 72 hrs) doses. Interestingly, beneficial effects of DCS were reported in a range of animal models of human diseases as well as in several clinical indications thought to involve disruptions in NMDAR function, such as drug addiction, post-traumatic stress disorder, Parkinson's disease, aging and psychiatric disorders. As DCS has a good safety profile, and is already in use in humans in several different indications, and based on studies with DCS in the mouse TBI model, a multi-center prospective randomized controlled clinical trial, aiming to assess the effect of a single dose of DCS on cognitive outcome in patients with moderate TBI has recently begun.
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CNS Neurol Disord Drug Targets · Jan 2014
ReviewInteraction of different proteins with GABAA receptor and their modulatory effect on inhibitory neural transmission leads to epilepsy.
γ-Aminobutyric acid type A receptors (GABAARs) are key players in the mediation of synaptic inhibition in the mammalian brain. Several proteins have a significant role in the complex trafficking mechanisms of GABAARs to and from the neuronal surface. Proper trafficking maintain number and localization of GABAAR at the neuronal surface which is necessary for inhibitory neuronal transmission. ⋯ Deletion in the KIF5A can impair transportation mechanism of GABAAR, while an inappropriate inhibitory GABAAR mediated neuronal transmission leads to epilepsy. In this article, we discussed the dynamic regulation of GABAAR, role of different proteins in GABAAR trafficking, clustering and endocytosis by direct interaction with GABAAR or interaction through adaptor proteins linked with microtubules and also the dysregulation of GABAAR trafficking in epilepsy. It is concluded that various proteins are involved in the GABAAR trafficking; mutation or any other change in the interacting proteins can reduce the GABAAR trafficking and also reduces their cell surface expression which may lead to epilepsy.
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CNS Neurol Disord Drug Targets · Jan 2014
Identification of potent caspase-3 inhibitors for treatment of multi- neurodegenerative diseases using pharmacophore modeling and docking approaches.
Neurodegenerative disorders are due to excessive neuronal apoptosis and the caspase-3 plays a key role in the apoptotic pathway. The caspase-3 inhibition may be a validated therapeutic approach for neurodegenerative disorders and an interesting target for molecular modeling studies using both Ligand and structure based approaches. In view of the above we have generated the Ligand based pharmacophore model using the Discovery studio 2.0 software. ⋯ Two ligands, ZINC12405015 and ZINC12405043 were finally selected on the basis of their fit values and docking scores. This study also reveals the important amino acids viz. His-121, Ser-205, Arg-207 which were found to be playing crucial role in the binding of the selected compounds within the active site of caspase-3.