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Abstract: In previous studies, inhibition of mitogen-activated protein kinase (MAP) p38 significantly improved recovery and attenuated apoptosis after retinal ischemia in rats. Yet, ischemic preconditioning (IPC) attenuated the ischemia-induced increase in p38 expression. We hypothesized that p38 was required for induction of ischemic tolerance by IPC. We examined the mechanisms of involvement of p38 in IPC neuroprotection. IPC or ischemia was induced in rat retina in vivo. Recovery after ischemia performed 24h after IPC was assessed functionally (electroretinography) and histologically at 7d after ischemia in the presence or absence of inhibition of p38. We examined the role of p38α in the mimicking of IPC produced by opening mitochondrial KATP channels using diazoxide, or stimulation of p38 activation by anisomycin. The importance of adenosine receptors in p38 activation after IPC was assessed using specific blockers of adenosine A1 and A2a receptors. Interfering RNA (siRNA) or SB203580 was used to block p38α. Phosphorylated p38 levels were measured. Phosphorylated p38 protein increased with IPC. Interfering RNA (siRNA) to p38α prior to IPC, or inhibiting p38 activation with SB203580, with ischemia following 24h later, significantly attenuated the neuroprotective effect of IPC. Anisomycin administered to increase p38 mimicked IPC, an effect blocked by SB203580. IPC-mimicking with diazoxide, an opener of mitochondrial KATP channels, was diminished with p38α siRNA. Adenosine receptor blockade did not decrease the elevated levels of phosphorylated p38 after IPC. Specific inhibition of p38α suggests that this MAPK is involved in the protective effects of IPC, and that p38 is downstream of mitochondrial KATP channels, but not adenosine receptors, in this neuroprotection. [Copyright &y& Elsevier]

Abstract: The importance of cytokines and the complement system in the propagation and maintenance of the brain inflammatory response to injury are emphasised. Much data supports the case that ischemia and trauma elicit an inflammatory response in the injured brain. This inflammatory response consists of mediators (cytokines, complement activation, chemokines and adhesion molecules) followed by cells (neutrophils early after the onset of brain injury and then a later monocyte infiltration). De novo up-regulation of pro-inflammatory cytokines, chemokines and endothelial-leukocyte adhesion molecules occurs soon following focal ischemia and trauma and at a time when the tissue injury is evolving. The significance of this brain inflammatory response and its contribution to brain injury is now better understood. In this review, we discuss the role of TNFα and IL-1β in traumatic and brain injury and associated inflammation, and the co-operative actions of the complement system, chemokines and adhesion molecules in this process. Celluar stress and cellular stress signalling is key to the neurodegenerative process in brain injury. Therefore, we also address novel approaches to target cytokines and reduce the brain inflammatory response, and thus brain injury, in stroke and neurotrauma. The mitogen-activated protein kinase (MAPK), p38, has been linked to inflammatory cytokine production and cell death following cellular stress. Stroke-induced p38 enzyme activation in the brain has been demonstrated, and treatment with p38 MAPK inhibitors can provide a significant reduction in infarct size, neurological deficits and increased inflammatory cytokines/proteins expression produced by focal stroke. p38 MAPK inhibition can also provide direct protection of cultured brain tissue to in vitro ischemia. This robust neuroprotection that can be produced by inhibition of p38 MAPK signalling emphasizes a significant opportunity for targeting MAPK pathways CNS injury/disease. Many examples of the roles of inflammation, cellular oxidative stress and MAPK signalling in Psychiatric and Neurodegenerative Diseases are also provided. As a whole, the available data suggests that inflammation, cellular stress and p38 MAPK signalling are important in nervous disease pathologies and that inhibition of cellular stress signalling should be considered for improving outcome in many CNS diseases. [Copyright &y& Elsevier]

Background: In vitro evidence suggests that the p38 mitogen-activated protein kinase (p38 MAPK) plays a crucial role in PMN activation and inflammatory cytokine production. However, the effect of p38 MAPK on myocardial reperfusion injury, a pathologic condition involving a typical inflammatory response, has not been fully examined. In the present study, we investigated the effect of SB 239063, a specific p38 MAPK inhibitor, on myocardial injury in a murine ischemia/reperfusion (I/R) model and elucidated the mechanism by which p38 MAPK inhibitor may exert its protective effect against I/R injury. Methods and results: I/R resulted in a significant myocardial injury (myocardial infarct 45±2.9%) and marked PMN accumulation (myeloperoxidase activity 1.03±0.16 U/100 g tissue). Administration of SB 239063 significantly inhibited the myocardial inflammatory response as evidenced by reduced PMN accumulation in I/R myocardial tissue (0.62±0.008 U/100 g tissue, P<0.01 vs. vehicle), and markedly attenuated myocardial reperfusion injury (myocardial infarct size: 28±2.4%, P<0.01 vs. vehicle). Moreover, treatment with SB 239063 significantly attenuated I/R-induced P-selectin and ICAM-1 upregulation (13.8±2.7 vs. 23.9±3.1%, and 29.4±1.6 vs. 56.3±4.8%, respectively P<0.01). In addition, pre-treatment with R15.7, a monoclonal antibody against CD 18 adhesion molecule on PMN surface that virtually abolished PMN accumulation in ischemic-reperfused myocardial tissue, significantly, but not completely, blocked the cardioprotection exerted by SB 239063. Conclusion: These results demonstrated for the first time that p38 MAPK activation plays a significant role in adhesion molecule upregulation on ischemia-reperfused endothelial cells and is an important signaling step in the pathogenesis of PMN-mediated tissue injury. [Copyright &y& Elsevier]

The neuroprotective effects of isradipine, a 2,4-dihydropyridine calcium channel blocker, has been well studied in the rat model of focal ischemia (induced by middle cerebral artery occlusion, MCAO). The present study was designed to evaluate whether isradipine pretreatment caused early (0–3 h after stroke) ischemic changes in diffusion- weighted magnetic resonance imaging (DWI) and if such changes were predictive of previously documented protection in brain infarction. An initial dose-response study using neurological deficit scores and estimates of protection from brain infarction (by histology) showed that isradipine reduced cortical infarctions compared to vehicle-treated animals at most doses (between 1.25 and 5 mg/kg/day s.c. for 6 days) with the best results obtained at 5 mg/kg/day, where a 78.5% reduction was observed. This dose was utilized to perform the DWI study. Early quantitative estimates of infarct size, as measured by DWI at 1, 2 and 3 h after MCAO, were similar to those obtained with late histology at 24 h. These data indicate that in pretreatment protocols, DWI can be used to quantitatively predict areas at risk of permanent damage. This work also demonstrates that neurological deficits, developing from the damaged forebrain following focal stroke, may provide an index of isradipine’s neuroprotective activity. [ABSTRACT FROM AUTHOR]

Stroke-prone rat strains exhibit an increased stroke risk and sensitivity, and reduced endogenous mechanisms of ischemic brain tolerance. This experiment provides a comparative, serial evaluation of neurological deficits and brain injury following middle cerebral artery occlusion/permanent focal stroke in this high-risk strain. Stroke-prone spontaneously hypertensive (SHR-SP), spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats were evaluated over 28 days using magnetic resonance imaging (MRI), histopathology, and neurobehavioral testing. T2- and diffusion weighted-MRI was performed after 1, 10 and 28 days to measure the degree of stroke-induced brain injury. Normotensive WKY rats receiving the same stroke and other SHR-SP rats receiving sham surgery were used for control comparisons. Functional deficits were scored after 1, 4, 11, 18 and 28 days. The degree of brain infarction/injury was practically identical in hypertensive and stroke-prone rats. WKY rats exhibited significantly smaller infarcts (P<0.05), with neurological function recovering quickly to normal by day 11 in this strain. Functional deficits persisted longer in hypertensive rats, with function recovering to normal by day 18 (P<0.05). Functional deficits in SHR-SP rats persisted the longest, and were observed even after 28 days (P<0.05). This increased and prolonged neurologic dysfunction exhibited by SHR-SP compared to SHR rats, while exhibiting practically identical degrees of brain injury/infarction, reflects the increased stroke risk and sensitivity of this strain and suggests a reduced SHR-SP brain plasticity following injury. Therefore, the stroke-prone rat provides an enhanced and prolonged functional deficit model that can be used to elucidate those mechanisms/novel targets critical to longitudinal neurobehavioral recovery post-stroke. [Copyright &y& Elsevier]