Rodent Gymnastics: Neurobehavioral Assays in Ischemic Stroke.

Despite years of research, most preclinical trials on ischemic stroke have remained unsuccessful owing to poor methodological and statistical standards leading to "translational roadblocks." Various behavioral tests have been established to evaluate traits such as sensorimotor function, cognitive and social interactions, and anxiety-like and depression-like behavior. A test's validity is of cardinal importance as it influences the chance of a successful translation of preclinical results to clinical settings. The mission of choosing a behavioral test for a particular project is, therefore, imperative and the present review aims to provide a structured way to evaluate rodent behavioral tests with implications in ischemic stroke.

Role of KCa3.1 Channels in CNS Diseases: A Concise Review.

KCa3.1 protein is part of a heterotetrameric voltage-independent potassium channel, the activity of which depends on the intracellular calcium binding to calmodulin. KCa3.1 is immensely significant in regulating immune responses and primarily expressed in cells of hematopoietic lineage. It is one of the attractive pharmacological targets that are known to inhibit neuroinflammation. KCa3.1 blockers mediate neuroprotection through multiple mechanisms, such as by targeting microglia-mediated neuronal killing. KCa3.1 modulators may provide alternative treatment options for neurological disorders like ischemic stroke, Alzheimer disease, glioblastoma multiforme, multiple sclerosis and spinal cord injury. This review is an attempt to draw attention towards KCa3.1 channel, which was never exploited to its full potential as a viable therapeutic candidate against various neurological disorders.

CypD: The Key to the Death Door.

Numerous studies have deciphered the importance of Cyclophilin D (CypD/ peptidyl prolyl cis-trans isomerase F) in the formation and regulation of mitochondrial permeability transition pore (MPTP), implicated in the cell death mechanisms in various neurological diseases. Decrease in the ATP and increase in the calcium levels are the most common aftermath consequences that are observed in these diseases. Increased calcium level leads to the persistent opening of MPTP and cell death, which is mediated by CypD. However, the underlying mechanisms that contribute to the abnormal calcium homeostasis in different diseases remain elusive. In this review, we attempted to connect the disruption of mitochondrial bioenergetics with abnormal calcium levels and MPTP. Further, various proteins that interact with the CypD and the subsequent consequences have been described. All the cell death pathways in various neurological disorders merge at CypD, which acts as a key regulatory protein in cellular demise. Agents inhibiting CypD may have a therapeutic potential for treating neurological disorders such as Alzheimer's disease, Parkinson's disease and cerebral ischemia. Further, the knowledge regarding the pathophysiological processes involved in CypD-regulated MPTP and cell death would assist in battling with these diseases.

Generation of pharmacophore and atom based 3D-QSAR model of novel isoquinolin-1-one and quinazolin-4-one-type inhibitors of TNFα.

In the present report, 3D-QSAR analysis was executed on the previously synthesized and evaluated derivatives of isoquinolin-1-ones and quinazolin-4-ones; potent inhibitors of tumor necrosis factor α (TNFα). Statistically significant 3D-QSAR models were generated using 42 molecules in the training set. The predictive ability of models was determined using a randomly chosen test set of 16 molecules, which gave excellent predictive correlation coefficients for 3-D models, suggesting good predictive index. Pharmacophore prediction generated a five point pharmacophore (AAHRR): two hydrogen bond acceptor (A), one hydrophobic (H) and two ring (RR) features. This pharmacophore hypothesis furnished a statistically meaningful 3D-QSAR model with partial least-square (PLS) factors seven having R2=0.9965, Q2=0.6185, Root Mean Squared Error=0.4284 and Pearson-R=0.853. Docking study revealed the important amino acid residues (His 15, Tyr 59, Tyr 151, Gly 121 and Gly 122) in the active site of TNFα that are involved in binding of the active ligand. Orientation of the pharmacophore hypothesis AAHRR.25 corresponded very closely with the binding mode recorded in the active site of ligand bound complex. The results of ligand based pharmacophore hypothesis and atom based 3D-QSAR furnished crucial structural insights and also highlighted the important binding features of isoquinolin-1-ones and quinazolin-4-ones derivatives, which may provide guidance for the rational design of novel and more potent TNFα inhibitors.

Asiatic acid, a pentacyclic triterpene from Centella asiatica, is neuroprotective in a mouse model of focal cerebral ischemia.

Asiatic acid, a triterpenoid derivative from Centella asiatica, has shown biological effects such as antioxidant, antiinflammatory, and protection against glutamate- or beta-amyloid-induced neurotoxicity. We investigated the neuroprotective effect of asiatic acid in a mouse model of permanent cerebral ischemia. Various doses of asiatic acid (30, 75, or 165 mg/kg) were administered orally at 1 hr pre- and 3, 10, and 20 hr postischemia, and infarct volume and behavioral deficits were evaluated at day 1 or 7 postischemia. IgG (blood-brain barrier integrity) and cytochrome c (apoptosis) immunostaining was carried out at 24 hr postischemia. The effect of asiatic acid on stress-induced cytochrome c release was examined in isolated mitochondrial fractions. Furthermore, its effects on cell viability and mitochondrial membrane potential were studied in HT-22 cells exposed to oxygen-glucose deprivation. Asiatic acid significantly reduced the infarct volume by 60% at day 1 and by 26% at day 7 postischemia and improved neurological outcome at 24 hr postischemia. Our studies also showed that the neuroprotective properties of asiatic acid might be mediated in part through decreased blood-brain barrier permeability and reduction in mitochondrial injury. The present study suggests that asiatic acid may be useful in the treatment of cerebral ischemia.