Investigation on beneficial role of l-carnosine in neuroprotective mechanism of ischemic postconditioning in mice: possible role of histidine histamine pathway.

OBJECTIVE: The present study was undertaken to investigate the possible role of histidine-histamine pathway in the neuroprotective effects produced by L-carnosine hand in hand with ischemic postconditioning in the animal model of cerebral ischemia. METHODS: Cerebral ischemia was induced in swiss albino mice by performing BCCAO surgery. Morris water-maze test was utilized to assess the learning ability and memory of the animals. The whole brain acetylcholinesterase (AChE) activity, TBARS, GSH levels and MPO activity were evaluated as the biochemical parameters. For histopathological evaluation of the cerebral infarct size, TTC staining was employed. RESULTS: Administration of L-carnosine (500 mg/kg, i.p.) successfully attenuated the manifestations of cerebral ischemia. Higher levels of AChE, TBARS, and MPO were observed in BCCAO treated animals, which were successfully attenuated by treatment with L-carnosine and ischemic postconditioning. Whereas administration of L-carnosine and ischemic postconditioning significantly increased the level of GSH in BCCAO treated animals. Moreover, treatment with ranitidine, an H2 blocker (30 NMol, i.c.v) antagonized the neuroprotective actions of L-carnosine evidenced by decrease in MWM performance, increase in the level of AChE and oxidative stress, while decrease in GSH level in brain. The cerebral infarct size was found to be more in BCCAO inflicted animals, which was improved by the administration of L-carnosine, while the cerebral infarct size worsened by treatment with ranitidine (3 nmol, i.c.v.). CONCLUSION: It is concluded that L-carnosine exerts neuroprotective effect via involvement of histidine-histamine pathway since the beneficial effects of L-carnosine were abolished by the H2-blocker.

Diabetes abolish cardioprotective effects of remote ischemic conditioning: evidences and possible mechanisms.

Diabetes mellitus significantly hampers the development of cardioprotective response to remote pre/post/perconditioning stimuli by impairing the activation of cardioprotective signaling pathways. Among the different pathways, the impairment in O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling and release of cardioprotective humoral factor may contribute in attenuating remote preconditioning-induced cardioprotection. Moreover, the failure to phosphorylate extracellular signal related kinase (ERK), phosphoinositide-3-kinase (PI3K), and AKT along with up-regulation of mechanistic target of rapamycin (mTOR) and decrease in autophagy may also attenuate remote preconditioning-induced cardioprotection. Remote perconditioning stimulus also fails to phosphorylate AKT kinase in diabetic heart. In addition, diabetes may increase the oxidative stress, reactive oxygen species (ROS) production, decrease the beclin expression, and inhibit autophagy to attenuate remote perconditioning-induced cardioprotection. Moreover, diabetes-induced increase in the Rho-associated kinase (ROCK) activity, decrease in the arginase activity, and reduction in nitric oxide (NO) bioavailability may also contribute in decreasing remote perconditioning-induced cardioprotection. Diabetes may reduce the phosphorylation of adenosine 5'-monophosphate activated protein kinase (AMPKα) and increase the phosphorylation of mTOR to attenuate cardioprotection of remote postconditioning. The present review describes the role of diabetes in attenuating remote ischemic conditioning-induced cardioprotection along with the possible mechanisms.

Animals models of spinal cord contusion injury.

Spinal cord contusion injury is one of the most serious nervous system disorders, characterized by high morbidity and disability. To mimic spinal cord contusion in humans, various animal models of spinal contusion injury have been developed. These models have been developed in rats, mice, and monkeys. However, most of these models are developed using rats. Two types of animal models, i.e. bilateral contusion injury and unilateral contusion injury models, are developed using either a weight drop method or impactor method. In the weight drop method, a specific weight or a rod, having a specific weight and diameter, is dropped from a specific height on to the exposed spinal cord. Low intensity injury is produced by dropping a 5 g weight from a height of 8 cm, moderate injury by dropping 10 g weight from a height of 12.5-25 mm, and high intensity injury by dropping a 25 g weight from a height of 50 mm. In the impactor method, injury is produced through an impactor by delivering a specific force to the exposed spinal cord area. Mild injury is produced by delivering 100 ± 5 kdyn of force, moderate injury by delivering 200 ± 10 kdyn of force, and severe injury by delivering 300 ± 10 kdyn of force. The contusion injury produces a significant development of locomotor dysfunction, which is generally evident from the 0-14th day of surgery and is at its peak after the 28-56th day. The present review discusses different animal models of spinal contusion injury.

Exploring the role and inter-relationship among nitric oxide, opioids, and KATP channels in the signaling pathway underlying remote ischemic preconditioning induced cardioprotection in rats.

OBJECTIVES: This study explored the inter-relationship among nitric oxide, opioids, and KATP channels in the signaling pathway underlying remote ischemic preconditioning (RIPC) conferred cardioprotection. MATERIALS AND METHODS: Blood pressure cuff was placed around the hind limb of the animal and RIPC was performed by 4 cycles of inflation (5 min) followed by deflation (5 min). An ex vivo Langendorff's isolated rat heart model was used to induce ischemia (of 30 min duration)-reperfusion (of 120 min duration) injury. RESULTS: RIPC significantly decreased ischemia-reperfusion associated injury assessed by decrease in myocardial infarct, LDH and CK release, improvement in postischemic left ventricular function, LVDP, dp/dtmax, and dp/dtmin. Pretreatment with L-NAME and naloxone abolished RIPC-induced cardioprotection. Moreover, preconditioning with sodium nitroprusside (SNP) and morphine produced a cardioprotective effect in a similar manner to RIPC. L-NAME, but not naloxone, attenuated RIPC and SNP preconditioning-induced increase in serum nitrite levels. Morphine preconditioning did not increase the NO levels, probably suggesting that opioids may be the downstream mediators of NO. Furthermore, glibenclamide and naloxone blocked cardioprotection conferred by morphine and SNP, respectively. CONCLUSION: It may be proposed that the actions of NO, opioids, and KATP channels are interlinked. It is possible to suggest that RIPC may induce the release of NO from endothelium, which may trigger the synthesis of endogenous opioids, which in turn may activate heart localized KATP channels to induce cardioprotection.

Conditioning-induced cardioprotection: Aging as a confounding factor.

The aging process induces a plethora of changes in the body including alterations in hormonal regulation and metabolism in various organs including the heart. Aging is associated with marked increase in the vulnerability of the heart to ischemia-reperfusion injury. Furthermore, it significantly hampers the development of adaptive response to various forms of conditioning stimuli (pre/post/remote conditioning). Aging significantly impairs the activation of signaling pathways that mediate preconditioning-induced cardioprotection. It possibly impairs the uptake and release of adenosine, decreases the number of adenosine transporter sites and down-regulates the transcription of adenosine receptors in the myocardium to attenuate adenosine-mediated cardioprotection. Furthermore, aging decreases the expression of peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α) and subsequent transcription of catalase enzyme which subsequently increases the oxidative stress and decreases the responsiveness to preconditioning stimuli in the senescent diabetic hearts. In addition, in the aged rat hearts, the conditioning stimulus fails to phosphorylate Akt kinase that is required for mediating cardioprotective signaling in the heart. Moreover, aging increases the concentration of Na+ and K+, connexin expression and caveolin abundance in the myocardium and increases the susceptibility to ischemia-reperfusion injury. In addition, aging also reduces the responsiveness to conditioning stimuli possibly due to reduced kinase signaling and reduced STAT-3 phosphorylation. However, aging is associated with an increase in MKP-1 phosphorylation, which dephosphorylates (deactivates) mitogen activated protein kinase that is involved in cardioprotective signaling. The present review describes aging as one of the major confounding factors in attenuating remote ischemic preconditioning-induced cardioprotection along with the possible mechanisms.