Abstract
Chronic cerebral hypoperfusion during aging may cause progressive neurodegeneration as ischemic conditions persist. Proper functioning of the interplay between neurons and glia is fundamental for the functional organization of the brain. The aim of our research was to study the pathophysiological mechanisms, and particularly the derangement of the interplay between neurons and astrocytes-microglia with the formation of “triads,” in a model of chronic cerebral hypoperfusion induced by the two-vessel occlusion (2VO) in adult Wistar rats (n = 15). The protective effect of dipyridamole given during the early phases after 2VO (4 mg/kg/day i.v., the first 7 days after 2VO) was verified (n = 15). Sham-operated rats (n = 15) were used as controls. Immunofluorescent triple staining of neurons (NeuN), astrocytes (GFAP), and microglia (IBA1) was performed 90 days after 2VO. We found significantly higher amount of “ectopic” neurons, neuronal debris and apoptotic neurons in CA1 Str. Radiatum and Str. Pyramidale of 2VO rats. In CA1 Str. Radiatum of 2VO rats the amount of astrocytes (cells/mm2) did not increase. In some instances several astrocytes surrounded ectopic neurons and formed a “micro scar” around them. Astrocyte branches could infiltrate the cell body of ectopic neurons, and, together with activated microglia cells formed the “triads.” In the triad, significantly more numerous in CA1 Str. Radiatum of 2VO than in sham rats, astrocytes and microglia cooperated in the phagocytosis of ectopic neurons. These events might be common mechanisms underlying many neurodegenerative processes. The frequency to which they appear might depend upon, or might be the cause of, the burden and severity of neurodegeneration. Dypiridamole significantly reverted all the above described events. The protective effect of chronic administration of dipyridamole might be a consequence of its vasodilatory, antioxidant and anti-inflammatory role during the early phases after 2VO.
Highlights
Chronic ischemia is a progressive neurodegenerative process caused by cerebral hypoperfusion that may manifest with cognitive dysfunction as ischemic conditions persist (Sarti et al, 2002b; Schmidt-Kastner et al, 2005; Melani et al, 2010)
We previously demonstrated in two different animal models of neurodegeneration that astrocytes and microglia appear to collaborate in the clearance of apoptotic neurons and neuronal debris in the CA1 region of the hippocampus (Cerbai et al, 2012)
Using the novel method of simultaneous triple immunostaining of neurons, astrocytes and microglia, we further characterized the interplay among neurons and glia in this animal model of chronic cerebral hypoperfusion and neurodegeneration
Summary
Chronic ischemia is a progressive neurodegenerative process caused by cerebral hypoperfusion that may manifest with cognitive dysfunction as ischemic conditions persist (Sarti et al, 2002b; Schmidt-Kastner et al, 2005; Melani et al, 2010). Agerelated cerebrovascular stenosis caused by arteriosclerosis induces failure of brain circulation, and resolution of cerebral hypoperfusion has been reported to improve mental decline in humans (Hirono et al, 1993; Nencini et al, 1993; Tsuda et al, 1994; Tatemichi et al, 1995). For the reproduction of chronic cerebral hypoperfusion as it occurs in human aging, the permanent, bilateral occlusion of the common carotid arteries in rats (two-vessel occlusion, 2VO) is a widely recognized procedure that allows to investigate the mechanisms that link chronic cerebral hypoperfusion to neurodegenerative processes (Sarti et al, 2002a,b; Farkas et al, 2007). The CA1 region of the hippocampus is vulnerable to ischemia and to the 2VO-related pattern of hypoperfusion and metabolic changes, leading to failure of neuronal signaling, and to learning and memory disturbances
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