Loss of substance P and inflammation precede delayed neurodegeneration in the substantia nigra after cerebral ischemia

Abstract

Focal cerebral ischemia leads to delayed neurodegeneration in remote brain regions. The substantia nigra (SN) does not normally show primary neuronal death after ischemic events affecting the striatum, but can exhibit delayed neuronal loss after the ischemic injury through mechanisms that are unknown. No data are available in mice showing acute post-stroke inflammation and remote injury in the SN. Substance P (SP), a mediator of neurogenic inflammation, is a key element of the striato-nigral circuitry, but alterations of SP in the SN have not been studied after acute striatal injury. Inflammation, a key contributor to neuronal death, is found in the SN after striatal ischemia, but it is unknown whether it precedes or occurs concomitantly with neuronal death. We hypothesised that focal striatal ischemia induces changes in SP levels in the SN and that inflammation precedes neuronal death in the SN. Using the middle cerebral artery occlusion model, we found a significant loss of SP in the ipsilateral SN 24h after striatal ischemia in mice. In the same area where SP loss occurs, significant glial and vascular activation, but no neuronal death, were observed. In contrast, a marked neuronal loss was observed within six days in the area of SP loss and inflammation. Our data suggest that focal loss of SP and early inflammatory changes in the SN precede remote neuronal injury after striatal ischemic damage. These observations may have important implications for motor impairment in stroke patients and indicate that striatal ischemia might facilitate Parkinson's disease development.