Stroke in normotensive and hypertensive rats : effects of Lithium and inhibitors of the renin-angiotensin system
In the present study, the effect of lithium alone or in combination with the ACE inhibitor, captopril or the AT1 receptor antagonist, telmisartan, were investigated in two animal models of stroke: First, the stroke-prone spontaneously hypertensive rat (SHRSP), an animal model of severe hypertension associated with the development of cerebral, renal and cardiac dysfunction. In these animals, the onset of stroke is accelerated by salt-loading.. Second, a model of focal cerebral ischemia with 90 min occlusion of the middle cerebral artery (MCAO) followed by reperfusion. In the first set of experiment, we demonstrate that renin-angiotensin system (RAS) inhibitors markedly prolong survival time in salt-loaded SHRSP, and majority of animals not longer die from stroke after treatment with RAS inhibitors. RAS inhibitors reduce the number of apoptotic/necrotic cells in the brain tissue after 5 weeks of treatment. Lithium does not improve the effect of sufficiently dosed RAS inhibitors. In the secondary set of experiment, chronic treatment with lithium decreases the infarct volume and improves the neurological outcome in the normotensive Wistar rats with transient MCAO. The neuroprotective effects of lithium are associated with a reduction of activated caspase-3 expression and inhibition of DNA fragmentation in the ischemic penumbra of the brain cortex. RAS inhibitors do not influence the neurological deficits and infarct volume in these animals. RAS inhibitors reduce apoptosis and the degree of microglial activation in the ischemic penumbra of the brain cortex. However, there are no synergistic effects between RAS inhibitors and lithium in the rats with focal cerebral ischemia.