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Abstract: The resin of Boswellia species is a major anti-inflammatory agent that has been used for centuries to treat various conditions including injuries and inflammatory conditions. Incensole acetate (IA), a major constituent of this resin, has been shown to inhibit NF-κB activation and concomitant inflammation, as well as the neurological deficit following head trauma. Here, we show that IA protects against ischemic neuronal damage and reperfusion injury in mice, attenuating the inflammatory nature of ischemic damage. IA given post-ischemia, reduced infarct volumes and improved neurological activities in the mouse model of ischemic injury in a dose dependent fashion. The protection from damage was accompanied by inhibition of TNF-α, IL-1β and TGF-β expression, as well as NF-κB activation following injury. In addition, IA is shown to have a therapeutic window of treatment up to 6h after ischemic injury. Finally, the protective effects of IA were partially mediated by TRPV3 channels as determined by the TRPV3 deficient mice and channel blocker studies. This study suggests that the anti-inflammatory and neuroprotective activities of IA may serve as a novel therapeutic treatment for ischemic and reperfusion injury, and as a tool in the ongoing research of mechanisms for neurological damage. [Copyright &y& Elsevier]

Abstract: Motoneuronotrophic factor (MNTF) is an endogenous neurotrophin that is highly specific for the human nervous system, and some of the observed effects of MNTF include motoneuron differentiation, maintenance, survival, and reinnervation of target muscles and organs. MNTF is a neuro-signaling molecule that binds to specific receptors. Using In Silico Analysis, one of the active sites of MNTF was identified as an analog of six amino acids (GM6). The effect of chemically synthesized GM6 on ischemic stroke was studied in the middle cerebral artery occlusion (MCAo) mouse model. Mice were subjected to 1 hur of ischemia followed by 24 h of reperfusion. Mice were injected intravenously with a bolus of GM6, at various doses (1 and 5 mg/kg) immediately after the start of reperfusion and examined for changes in physiological parameters, neurological deficits and infarct volume. GM6 was able to penetrate the blood brain barrier, and at both 1 and 5 mg/kg showed a significant protection from infarct damage, which translated to improvement of neurological deficits. Administration of GM6 demonstrated no changes in HR, BP, pO2, pCO2, or pH. A significant increase over the control group in CBF after reperfusion was observed with GM6 administration, which helped to mitigate the ischemic effect caused by the blockage of blood flow. The time window of treatment was assessed at various times following cerebral ischemia with GM6 demonstrating a significant protective effect up to 6–12 h post ischemia. In addition, GM6 increased neurogenesis, and decreased apoptosis and inflammation in the mouse brain following cerebral ischemic injury. These data suggest that GM6 is neuroprotective to the brain following IV injection in the mouse model of MCAo. [Copyright &y& Elsevier]

A cardinal feature of brain tissue injury in stroke is mitochondrial dysfunction leading to cell death, yet remarkably little is known about the mechanisms underlying mitochondrial injury in cerebral ischemia/reperfusion (IR). Ceramide, a naturally occurring membrane sphingolipid, functions as an important second messenger in apoptosis signaling and is generated by de novo synthesis, sphingomyelin hydrolysis, or recycling of sphingolipids. In this study, cerebral IR-induced ceramide elevation resulted from ceramide biosynthesis rather than from hydrolysis of sphingomyelin. Investigation of intracellular sites of ceramide accumulation revealed the elevation of ceramide in mitochondria because of activation of mitochondrial ceramide synthase via post-translational mechanisms. Furthermore, ceramide accumulation appears to cause mitochondrial respiratory chain damage that could be mimicked by exogenously added natural ceramide to mitochondria. The effect of ceramide on mitochondria was somewhat specific; dihydroceramide, a structure closely related to ceramide, did not inflict damage. Stimulation of ceramide biosynthesis seems to be under control of JNK3 signaling: IR-induced ceramide generation and respiratory chain damage was abolished in mitochondria of JNK3-deficient mice, which exhibited reduced infarct volume after IR. These studies suggest that the hallmark of mitochondrial injury in cerebral IR, respiratory chain dysfunction, is caused by the accumulation of ceramide via stimulation of ceramide synthase activity in mitochondria, and that JNK3 has a pivotal role in regulation of ceramide biosynthesis in cerebral IR. [ABSTRACT FROM AUTHOR]