Selective Neuronal Vulnerability Following Mild Focal Brain Ischemia in the Mouse

Abstract

The evolution of cellular damage over time and the selective vulnerability of different neuronal subtypes was characterized in the striatum following 30‐minute middle cerebral artery occlusion and reperfusion in the mouse. Using autoradiography we found an increase in the density of [3H]PK11195 binding sites—likely reflecting microglial activation—in the lesion border at 3 days and in the whole striatum from 10 days to 6 weeks. This was accompanied by a distinct loss of [3H]flumazenil and [3H]CGP39653 binding sites from 10 days up to 6 weeks reflecting neuronal loss. Brain ischemia resulted in a substantial loss of medium spiny projection neurons as seen at three days by Nissl staining, TUNEL and immunocytochemistry using antibodies against microtubule‐associated protein (MAP2), NeuN, (μ‐opioid receptors, substance P, Lenkephalin, neurokinin B, choline acetyltransferase, parvalbumin, calretinin and somatostatin. Both patch and matrix compartments were involved in ischemic damage. In contrast, the numbers of cholinergic, GABAergic, and somatostatin‐containing interneurons in the ischemic striatum were not different from those in the contralateral hemisphere at 3 and 14 days. A low density of glutamate receptors, the ability to sequester calcium by calcium‐binding proteins and other hitherto unidentified factors may explain this relative resistance of interneurons to acute ischemia.

Influence of duration of focal cerebral ischemia and neuronal nitric oxide synthase on translocation of apoptosis-inducing factor to the nucleus

“…The delayed increase in nuclear AIF at 24 hours is consistent with the observation that cell death occurs over a period of days, and even weeks, when focal ischemic duration is brief (Du et al, 1996;Katchanov et al, 2003). For example, infarct volume in rats subjected to 30 minutes of MCAO plus bilateral common carotid artery occlusion increased between 3 days and 14 days of reperfusion to a size equivalent to that seen with 90 minutes of ischemia (Du et al, 1996).…”

Selective Neuronal Loss in Ischemic Stroke and Cerebrovascular Disease

“…These striking findings are reminiscent of Endres group's 30-minute proximal MCAo studies in mice reporting severe SNL (85% to 90% cell loss but sparing the interneurons) in the striatum at 3 weeks 45 and causing a 25% tissue atrophy at 10 weeks, 46 and of two other similar reports in rats. 40,39 These findings raise the intriguing possibility of an intrinsic difference regarding SNL between the cortex and striatum, such that neuron dropout in the latter may, under some as yet undetermined circumstances, slowly progress to very severe SNL over weeks.…”

“…45,46 Cortical SNL is of particular clinical relevance given that cortical lesions result in more enduring behavioral deficits, 47 and that the cortex is usually more prone to rescue by recanalization than the striatum owing to less profound ischemia. Temporary cortical ischemia can be achieved with either proximal or distal MCAo.…”

“…64 Although FMZ PET allows fully quantitative studies, 64,65 IMZ SPECT is affected by less favorable binding properties and tissue kinetics and worse spatial resolution and inaccurate attenuation correction, and hence provides less reliable data. 66 Although one in vitro 3 H-FMZ study and another ex vivo 123 I-IMZ rodent study have reported decreased cBZR binding in areas affected by SNL, 45,67 validation of in vivo binding as a surrogate for histopathologically defined SNL has been provided only recently in a rat study using FMZ PET 28 days after tMCAo. 17 Consistent with an in vitro rat study, 45 in one clinical study around 10 to 15 days elapsed until IMZ binding was maximally reduced in SNL areas, 68 suggesting that at least a fraction of the cBZRs remain for this time interval on doomed or already dead but not yet dismantled neurons.…”

“…when exactly the neurons die after reperfusion, is not well known, and systematic serial studies are missing, although in a mice study loss of NeuN labeling was already present 1 day after tMCAo. 45 At the biochemical level, the very high energy consumption of neurons makes them more sensitive to oxygen/glucose deprivation than other CNS cells, and hence more susceptible to ischemic injury during the occlusion phase; conversely, their very high postreperfusion mitochondrial activity would make them prone to oxygen radical production and damage. Also, glutamate excitotoxicity or glutamate/GABA imbalance are also more likely to affect neurons than glial cells.…”