Protective Effects Of Histamine On The Ischemia Induced By Oxygen-glucose Deprivation In Rat Hippocampal Slices And Protective Effects Of Cilostazol On Focal Cerebral Ischemia In Mice

Part â… Protective effects of histamine on the cellular edema and viability reduction induced by oxygen-glucose deprivation in rat hippocampal slicesIt has been reported that histamine is an important neurotransmitter or neuromodulator in the central nervous system, and exerts protective effects on cerebral ischemia. We, in this part, determined the effect of histamine on ischemia-induced cellular edema and viability reduction in rat hippocampal slices, and the involved subtypes of histamine receptor in this effect. In vitro ischemia injury was induced by oxygen and glucose deprivation (OGD) on hippocampal slices in rats. Various concentrations of histamine and/or piphenhydramine, an H₁ receptor antagonist, and cimetidine, an H₂ antagonist, were added into the medium 10 min before OGD, and maintained throughout the duration of OGD and recovery. The injury was determined by real-timely measuring the changes of light transmittance (LT) in CAl region of the hippocampal slices for the cellular edema, and by detecting the product of 2, 3, 5-triphenyltetrazolium chloride (TTC), formazan, for the slice viability. The effect ofhistamine at various concentrations on the injury was observed, and the blockage by the antagonists of histamine receptors was also investigated. We found that histamine (0.01-10 umol/L) inhibited the peak value of LT during OGD in hippocampal slices and improve the reduced viability after OGD. Diphenhydramine (0.1-10 umol/L) did not affect the effect of histamine, while cimetidine (0.1-10 umol/L) partly abolished the protective effect of histamine. We conclude that histamine protects hippocampal slices against ischemia-induced cellular edema and viability reduction;this effect might be mediated via H2 receptor.Part IIProtective effects of cilostazol, a phosphodiesterase-3 inhibitor, on focalcerebral ischemia induced by middle cerebral artery occlusion in miceIt has been reported that cilostazol, a selective phosphodiesterase-3 inhibitor, has protective effects on cerebral ischemia. We, in this part, further determined the neuroprotective effect of cilostazol on focal cerebral ischemia. Moreover, the dose- and time-dependencies of the effect of cilostazol were also assessed. Permanent focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in mice. Cilostazol was injected intraperitoneally 30 min before, or 1 h, 2 h, 3 h after MCAO, respectively. ONO-1078, a leukotriene antagonist, was used as the control. The neurological deficits, inclined board tests, infarct volumes, brain edema, survival neuron density, degenerated neuron density and IgG extravasation (blood-brain barrier dysfunction) were determined 24 h after MCAO. We found that cilostazol (3, 10 mg/kg) significantly attenuated all the ischemic insults. Post-treatment with cilostazol (10 mg/kg) at 1 h and 2 h after MCAO also significantly attenuated neurological deficits, decreased brain edema and infarct volume. However, post-treatment with cilostazol at 3 h after MCAO had no significant effect. We conclude that cilostazol has a dose- and time-dependent neuroprotective effect on the injury in the acute phase of focal cerebral ischemia in mice, with an effective dose range of 3-10 mg/kg and a therapeutic window of 1-2 h after ischemia. This effect might be partly related to the attenuation of vasogenic edema.Conclusions1. Histamine has protective effect on the in vitro ischemic injury induced by OGD in hippocampal slices of rats. Diphenhydramine, an Hi receptor antagonist, did not affect the effect of histamine. While, cimetidine, an H2 receptor antagonist, partly abolished the protective effect of histamine. We conclude that the protective effect of histamine might be mediated via H2 receptor.2. During 24 h after cerebral ischemia, cilostazol has a dose- and time-dependent neuroprotective effect on the injury in the acute phase of focal cerebral ischemia in mice, with an effective dose range of 3-10 mg/kg and a therapeutic window of 1-2 h after ischemia. This effect may be, at least partly, related to the attenuation of vasogenic edema.