Adaptive plasticity in tachykinin and tachykinin receptor expression afterfocal cerebral ischemia is differentially linked to GABAergic and glutamatergic cerebrocortical circuits and cerebrovenular endothelium

To test the hypothesis of an involvement of tachykinins in destabilization and hyperexcitation of neuronal circuits, gliosis, and neuroinflammation du ring cerebral ischemia, we investigated cell-specific expressional changes of the genes encoding substance P (SP), neurokinin B (NKB), and the tachyki nin/neurokinin receptors (NK1, NK2, and NK3) after middle cerebral artery o cclusion (MCAO) in the rat. Our analysis by quantitative in situ hybridizat ion, immunohistochemistry, and confocal microscopy was concentrated on cere brocortical areas that survive primary infarction but undergo secondary dam age. Here, SP-encoding preprotachykinin-A and NK1 mRNA levels and SP- like immunoreactivity were transiently increased in GABAergic interneurons at 2 d after MCAO. Coincidently, MCAO caused a marked expression of SP and NK1 i n a subpopulation of glutamatergic pyramidal cells, and in some neurons SP and NK1 mRNAs were coinduced. Elevated levels of the NKB-encoding preprotac hykinin-B mRNA and of NKB-like immunoreactivity at 2 and 7 d after MCAO wer e confined to GABAergic interneurons. In parallel, the expression of NK3 wa s markedly downregulated in pyramidal neurons. MCAO caused transient NK1 ex pression in activated cerebrovenular endothelium within and adjacent to the infarct. NK1 expression was absent from activated astroglia or microglia. The differential ischemia-induced plasticity of the tachykinin system in di stinct inhibitory and excitatory cerebrocortical circuits suggests that it may be involved in the balance of endogenous neuroprotection and neurotoxic ity by enhancing GABAergic inhibitory circuits or by facilitating glutamate -mediated hyperexcitability. The transient induction of NK1 in cerebrovenul ar endothelium may contribute to ischemia-induced edema and leukocyte diape desis. Brain tachykinin receptors are proposed as potential drug targets in stroke.