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The present study has been designed to investigate the possible role of histaminergic pathway in neuroprotective mechanism of ischemic postconditioning (iPoCo). Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 h was employed to produce I/R-induced cerebral injury in National Institutes of Health mice mice. iPoCo involving three episodes of carotid artery occlusion and reperfusion of 10 sec each was instituted immediately after BCAO just before prolonged reperfusion. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using Morris water maze test. Rotarod test, inclined beam-walking test, and neurological severity score (NSS) were performed to assess motor incoordination and sensorimotor abilities. Brain acetylcholine esterase (AChE) activity, brain myeloperoxidase (MPO) activity, brain thiobarbituric acid-reactive species (TBARS), and glutathione level (GSH) were also estimated. BCAO produced a significant rise in cerebral infarct size and NSS along with impairment of memory and motor coordination and biochemical alteration (↑AChE, ↑MPO ↓GSH, and ↑TBARS). iPoCo attenuated the deleterious effect of BCAO on infarct size, memory, NSS, motor coordination, and biochemical markers. Pretreatment of carnosine (a histamine [HA] precursor) potentiated the neuroprotective effects of iPoCo, whereas pretreatment of ketotifen (HA H1 receptor blocker and mast cell stabilizer) abolished the protective effects of iPoCo as well as that of carnosine on iPoCo. It may be concluded that neuroprotective effect of iPoCo probably involves activation of histaminergic pathways.

Src family kinases (SFKs), the largest family of nonreceptor tyrosine kinases, include 10 members. Src was the first gene product discovered to have intrinsic protein tyrosine kinase activity. Src is widely expressed in many cell types and can have different locations within a cell; the subcellular location of Src can affect its function. Src can associate with cellular membranes, such as the plasma membrane, the perinuclear membrane, and the endosomal membrane. SFKs actions on mammalian cells are pleiotropic and include effect on cell morphology, adhesion, migration, invasion, proliferation, differentiation, and survival. SFKs at one end have been documented to play some important physiological functions; on the other end, they have been described in the pathophysiology of some disorders. In this review article, an exhaustive attempt has been made to unearth pharmacology of SFKs and therapeutic implications of SFKs modulators.

Steroid sulfatase (STS) plays a momentous role in the conversion of sulfated steroids, which are biologically inactive, into biologically active un-sulfated steroid hormones, which support the development and growth of a number of hormone-dependent cancers, including breast cancer. Therefore, inhibitors of STS are supposed to be potential drugs for the treatment of breast and other steroid-dependent cancers. The present review concentrates on broad chemical classification of steroid sulfatase inhibitors. The inhibitors reviewed are classified into four main categories: Steroid sulfamate based inhibitors; Steroid non-sulfamate based inhibitors; Non-steroidal sulfamate based inhibitors; Non-steroidal non-sulfamate based inhibitors. A succinct overview of current treatment of cancer, estradiol precursors, STS enzyme and its role in breast cancer is herein described.

The present study was designed to investigate the possible role of endogenous opioids and KATP channels in glycerol-induced acute renal failure (ARF) in rats. The rats were subjected to rhabdomyolytic ARF by single intramuscular injection of hypertonic glycerol (50% v/v; 8 mL/kg), and the animals were sacrificed after 24 h of glycerol injection. The plasma creatinine, blood urea nitrogen, creatinine clearance, and histopathological studies were performed to assess the degree of renal injury. Naltrexone (2.5, 5.0 and 10.0 mg/kg s.c.), glibenclamide (5.0 and 10.0 mg/kg i.p.), and minoxidil (25 and 50 mg/kg) were employed to explore the role of endogenous opioids and KATP channels in rhabdomyolysis-induced ARF. Pretreatment with naltrexone and glibenclamide attenuated hypertonic glycerol-induced renal dysfunction in a dose-dependent manner, suggesting the role of endogenous opioids and KATP channels in the pathogenesis of myoglobuniric renal failure. However, the simultaneous pretreatment with naltrexone (10 mg/kg s.c.) and glibenclamide (10 mg/kg i.p.) did not enhance the reno-protective effects of individual drugs, suggesting that release of endogenous opioids and opening of KATP channels constitute a single pathway in acute renal injury triggered by hypertonic glycerol-induced rhabdomyolysis. Furthermore, administration of minoxidil abolished the attenuating effects of naltrexone in glycerol-induced renal failure, suggesting that opening of KATP channels is downstream to opioid receptor activation. It is concluded that hypertonic glycerol-induced rhabdomyolysis may involve release of endogenous opioids that in turn modulate KATP channels to contribute in the pathogenesis of ARF.

Animal models are pivotal for understanding the mechanism of neuropathic pain and development of effective therapy for its optimal management. A battery of neuropathic pain models has been developed to simulate the clinical pain conditions with diverse etiology. The present review exhaustively discusses the methodology, behavioral alterations, limitations, and advantages of about 40 different animal models of neuropathic pain along with their modifications. Development of these models has contributed immensely in understanding the chronic pain and underlying peripheral as well as central pathogenic mechanisms. Furthermore, research has resulted in the development of new therapeutic agents for neuropathic pain management, and the preclinical data obtained using these animal models have been successively translated to effective pain management in clinical setup also. As each animal model has been created with specific methodology and results tend to vary largely with the slight changes related to methodology, therefore, it is essential that data from different models should be reported and interpreted in the context of the specific pain model.

Preconditioning, a well established phenomenon had been used since 1980s to attenuate ischaemia-reperfusion induced injury. However, inability to predict the onset of ischaemia in clinical settings led to the discovery of a new concept of postconditioning (PoCo), in 2000s whereby brief repetitive cycles of ischaemia with intermittent reperfusion followed by prolonged ischaemia-elicited tissue protection. There is an impressive array of molecular mechanisms contributing to PoCo-mediated tissue-protection, which include triggers like adenosine (ADO), opioid, erythropoietin (EPO), endogenous nitric-oxide, reactive oxygen species, acetylcholine, tissue factors, pro-inflammatory cytokines and bradykinin; mediators like reperfusion injury salvage kinase pathways including phosphoinositide-3-kinase, extra-cellular signal regulated kinase(1/2) pathway, protein kinase G and protein kinase C; end-effectors like mitochondrial permeability transition pore and mitochondrial potassium ATP channel. The clinical applicability of PoCo has been extended with the use of PoCo mimetic agents like insulin, glucagon like peptide, EPO, statins and ADO before reperfusion in patients with ischaemia reperfusion injury. Remote PoCo has also emerged as a new concept; however, considerable research is required for understanding its molecular mechanisms. In this review, an exhaustive attempt has been made to unearth some molecular aspects of PoCo.

The present study was designed to investigate the ameliorative potential of Punica granatum in dextran sulfate sodium (DSS) induced ulcerative colitis. DSS (2%) was administered orally in drinking water for 7 days to induce ulcerative colitis. The extent and severity of ulceration was analysed macroscopically, histopathologically and using a disease activity index. Myeloperoxidase (MPO), a specific marker of inflammation; histamine, a marker of mast cell degranulation; superoxide anion generation and, lipid peroxides were analysed. Administration of DSS resulted in a significant development of ulceration in the colon along with a rise in histamine, MPO activity and oxidative stress. Treatment with Punica granatum extract and its ellagic acid rich fraction (100 mg/kg and 200 mg/kg p.o.) significantly attenuated DSS-induced colonic inflammation along with attenuation of histamine, MPO and oxidative stress. The antiulcerative effect of Punica granatum extract and its ellagic acid rich fraction were comparable to sulphasalazine (100 mg/kg, p.o.) and sodium cromoglycate (40 mg/kg i.p). It is concluded that Punica granatum has a potential for ameliorating DSS-induced colitis and its ellagic acid rich fraction may be responsible for this effect. Further, the antiulcerative effects may be attributed to mast cell stabilizing, antiinflammatory and antioxidant actions.

Remote ischemic preconditioning (RIPC) is a phenomenon whereby transient non-lethal ischemia and reperfusion episodes confer protection against prolonged ischemia-reperfusion-induced injury. However, the underlying intracellular signaling has not been extensively explored. The present study aims to inspect the putative involvement of TRPV1-dependent CGRP release in mediating remote hind limb preconditioning-induced cardioprotection. In the present study, remote hind limb preconditioning stimulus was delivered (4 consecutive episodes of 5 minutes of ischemia-reperfusion) using a blood pressure cuff tied at the inguinal level of the rat. The isolated rat hearts were perfused on the Langendorff's system and were subjected to 30 minutes global ischemia-120 minutes reperfusion. Prolonged ischemia and subsequent reperfusion led to myocardial injury that was evaluated in terms of infarct size, LDH release, CK release, LVDP, +dp/dtmax, -dp/dtmin and coronary flow rate. The pharmacological agents used in the present study included capsaicin as TRPV1 channel activator, sumatriptan and CGRP8-37 as CGRP blockers. Remote hind limb and capsaicin preconditioning (10 mg kg−1) significantly reduced the infarct size, LDH release, CK release and significantly improved LVDP, +dp/dtmax, -dp/dtmin and coronary flow rate. However, remote hind limb and capsaicin preconditioning-induced cardioprotective effects were remarkably reduced in the presence of sumatriptan (8 mg kg−1) and CGRP8-37 (1 mg kg−1). This indicates that remote hind limb preconditioning stimulus probably activates TRPV1 channels which subsequently induces CGRP release to produce cardioprotective effects. This article is protected by copyright. All rights reserved.