Cellular markers of neuroinflammation and neurogenesis after ischemic brain injury in the long-term survival rat model

Abstract

MRI was employed to follow the neurodegenerative foci and the localization of inflammatory cells by magnetically labeled CD4+ or CD8+ lymphocytes in the ischemia/reperfusion long-lived rats (9 and 13 months after 10 min of cardiac arrest). MRI of ischemic rats showed: (1) blood-brain barrier (BBB) leakage in the area of the dorsal hippocampus and brainstem-hindbrain level in basal cerebellum, (2) unlike anti-CD8 magnetic antibodies anti-CD4 ultra small paramagnetic iron oxide particles (USPIO) antibodies revealed hypointense areas in the brainstem-interbrain region and caudoputamen not found in animals that were not injected with USPIO antibodies, and (3) dilation in the retrosplenial area. Immunocytochemistry revealed microglial activation in the hippocampus and striatum, with indications of activation in thalamic lateral dorsal nuclei and the subventricular zone. In the CA1 and CA3 regions, it was noted that OX42- and ED1-positive granules appear in neuronal somata. Immunostaining of lymphocytes with TCR confirmed the T-cell presence in ischemic brain parenchyma of the hippocampus and striatum. The above observations thus point to a persistent dysfunction of BBB that in long-term may still lead to infiltration of T cells that are predominantly of helper (CD4+) type. Such inflammatory processes are backed by microglial activity even up to 1 year after ischemia/reperfusion. Moreover, in these animals an augmented expression of neurogenesis markers and neuroblast migration was also revealed in the subventricular zone. Thus, a balance of degenerative processes and inflammatory surveillance with neurogenesis could determine the long-term outcome of global ischemia survival or the previously proposed formation of amyloid plaques and Alzheimer's-type dementia.

Review paper Neurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin?

“…This change is based mostly on facts accumulated recently, indi-Ryszard Pluta, Anna Bogucka-Kocka, Marzena Ułamek-Kozioł, Wanda Furmaga-Jabłońska, Sławomir Januszewski, Judyta Brzozowska, Mirosław Jabłoński, Janusz Kocki cating that neural stem/progenitor cells occupy two main regions, the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus in the hippocampus, where they give rise to neurons after birth [30,38,54,58]. Neurogenesis has been found in these brain areas in all mammalian species, including humans [9,30,38,54,58], and may serve to replace brain cells damaged by insults. Two discrete brain regions presented contain progenitor cells that are capable of differentiating into neuronal or glial cells.…”

“…Since neurogenesis is required for memory and learning, and its activity has shown to be decreased after ischemia in humans and rodents [25,26], it has been suggested that impaired hippocampal neurogenesis might be an integral part of postischemic progression [58]. Particularly, a variety of key factors involved in brain ischemia, among them presenilin 1 and 2, amyloid precursor protein and its products β-amyloid peptides, play either a positive or a negative role in hippocampal neurogenesis [7,27].…”

“…A long-term study attempting to investigate neurogenesis was performed to assess ischemic neurogenic activity [58]. Moreover, numerous aspects of hippocampal neurogenesis, differentiation, and survival of neurons have not been uniformly addressed in the above studies, preventing straightforward comparisons.…”

“…The role of hippocampal neurogenesis in postischemic brain neurodegeneration It has been suggested that an increase in hippocampal neurogenesis might serve as a replacement mechanism for neuronal loss, thereby slowing down postischemic progression to dementia [24,58]. However, the native increase in hippocampal neurogenesis might not be sufficient to compensate for the massive ischemic neuronal loss [26,30,58].…”

“…However, the native increase in hippocampal neurogenesis might not be sufficient to compensate for the massive ischemic neuronal loss [26,30,58]. Recently, β-amyloid peptide oligomers have been reported to promote the generation of new neurons, but with no effect on cell survival [32].…”