Adaptive Plasticity in Tachykinin and Tachykinin Receptor Expression after Focal Cerebral Ischemia Is Differentially Linked to GABAergic and Glutamatergic Cerebrocortical Circuits and Cerebrovenular Endothelium

Abstract

To test the hypothesis of an involvement of tachykinins in destabilization and hyperexcitation of neuronal circuits, gliosis, and neuroinflammation during cerebral ischemia, we investigated cell-specific expressional changes of the genes encoding substance P (SP), neurokinin B (NKB), and the tachykinin/ neurokinin receptors (NK1, NK2, and NK3) after middle cerebral artery occlusion (MCAO) in the rat. Our analysis by quantitative in situ hybridization, immunohistochemistry, and confocal microscopy was concentrated on cerebrocortical areas that survive primary infarction but undergo secondary damage. 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 in a subpopulation of glutamatergic pyramidal cells, and in some neurons SP and NK1 mRNAs were coinduced. Elevated levels of the NKBencoding preprotachykinin-B mRNA and of NKB-like immunoreactivity at 2 and 7 d after MCAO were confined to GABAergic interneurons. In parallel, the expression of NK3 was markedly downregulated in pyramidal neurons. MCAO caused transient NK1 expression 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 distinct inhibitory and excitatory cerebrocortical circuits suggests that it may be involved in the balance of endogenous neuroprotection and neurotoxicity by enhancing GABAergic inhibitory circuits or by facilitating glutamate-mediated hyperexcitability. The transient induction of NK1 in cerebrovenular endothelium may contribute to ischemiainduced edema and leukocyte diapedesis. Brain tachykinin receptors are proposed as potential drug targets in stroke.

Neurokinin‐1 (NK‐1) receptor antagonists abrogate methamphetamine‐induced striatal dopaminergic neurotoxicity in the murine brain

“…The contribution of tachykinins in excitotoxic neurotransmission has been proposed for various pathological conditions in the nervous system, including nociception in spinal cord (Saria 1999), epilepsy in hippocampus (Liu et al 1999) and cerebral ischemia in cortex (Stumm et al 2001). Most recent studies demonstrated the co-localization of neuronal nitric oxide synthase (nNOS) and NK-1 receptor in striatal interneurons (Li et al 2001), as well as the direct projections from SP-containing neurons to nNOS-containing interneurons in the striatum (Li et al 2002).…”

Membrane Glycoprotein M6a Interacts with the μ-Opioid Receptor and Facilitates Receptor Endocytosis and Recycling

“…The coding sequences of M6a, M6b (GI: 9502118), and DM20 were amplified by PCR and then subcloned into the pGEM-T easy vector (Promega) for producing relative riboprobes. Generation of 35 S-labeled and digoxigeninlabeled riboprobes, hybridization, washing procedures, and detection of hybridization signals were performed as described (20). Hybridization signal densities of the sense probes were defined as background levels.…”

Somatostatin Receptor 2 Is Activated in Cortical Neurons and Contributes to Neurodegeneration after Focal Ischemia

“…Permanent MCAO and sham operation were performed in 6-week-old male Long-Evans rats (Mollegaard) as described previously (Culmsee et al, 1999;Stumm et al, 2001), with the modification that sodium pentobarbital was applied (40 mg/kg, i.p.) for anesthesia.…”

“…Densitometric analysis of hybridization signals and cell counts were conducted as described previously (Stumm et al, 2001) using NIH Image 1.62. For densitometry, sections of an experimental group, the respective control group, and a […”