Cofilin-actin rod formation in experimental stroke is attenuated by therapeutic hypothermia and overexpression of the inducible 70 kD inducible heat shock protein (Hsp70)

Abstract

Cofilin-actin rod formation in experimental stroke is attenuated by therapeutic hypothermia and overexpression of the inducible 70 kD inducible heat shock protein (Hsp70).Permalink https://escholarship.org/uc/item/2qb082g3 Journal Brain circulation, 5(4) Abstract:BACKGROUND AND PURPOSE: Cofilin-actin rods are covalently linked aggregates of cofilin-1 and actin. Under ischemic conditions, these rods have been observed in neuronal dendrites and axons and may contribute to the loss of these processes. Hypothermia (Hypo) and the 70 kD inducible heat shock protein (Hsp70) are both known to improve outcomes after stroke, but the mechanisms are uncertain.Here, we evaluated the effect of these factors on cofilin-actin rod formation in a mouse model of stroke. MATERIALS AND METHODS:Mice were subjected to distal middle cerebral artery occlusion (dMCAO) and treated with Hypo using a paradigm previously shown to be neuroprotective. We similarly studied mice that overexpressed transgenic (Tg) or were deficient knockout (Ko) in the inducible 70 kDa heat shock protein (Hsp70), also previously shown to be protective by our group and others. Cofilin-actin rod formation was assessed by histological analysis at 4 and 24 h after dMCAO. Its expression was analyzed in three different regions, namely, infarct core (the center of the infarct), middle cerebral artery (MCA) borderzone (the edge of the brain regions supplied by the MCA), and the ischemic borderzone (border of ischemic lesion). Ischemic lesion size and neurological deficits were also assessed. RESULTS:Both Hypo-treated and Hsp70 Tg mice had smaller lesion sizes and improved neurological outcomes, whereas Hsp70 Ko mice had larger lesion sizes and worsened neurological outcomes. Cofilin-actin rods were increased after stroke, but were reduced by therapeutic Hypo and in Hsp70 Tg mice. In contrast, cofilin-actin rods were increased in ischemic brains of Hsp70 Ko mice. CONCLUSIONS:Cofilin-actin rod formation was suppressed under the conditions of neuroprotection and increased under circumstances where outcome was worsened. This suggests that cofilin-actin rods may act to participate in or exacerbate ischemic pathology and warrants further study as a potential therapeutic target.

Cerebral Ischemia-Reperfusion Is Associated With Upregulation of Cofilin-1 in the Motor Cortex

“…Ischemia also leads to loss of dendrites and spines in neurons, even with survival of the parent cell body ( Tanay et al, 2006 ). Cofilin-actin rod suppression during the acute phase of ischemic stroke might provide neuroprotection with histological results ( Kurisu et al, 2019 ). It has also been reported that cofilin-1 increases in oxygen glucose deprivation model of ischemia with in vitro fetal mouse neurons ( Madineni et al, 2016 ).…”

Cofilin Signaling in the CNS Physiology and Neurodegeneration

“…The HSP70-deficient mice exhibited an increased cofilin-actin rod and a larger lesion size in the ischemic border zone. In contrast, HSP70 overexpression in transgenic mice reduced rod formation and improved neurological symptoms following stroke [ 128 ]. These reports indicate that cofilin is necessary during the recovery phase of stroke, and perturbed cofilin activity during this period might negatively affect the regenerative process.…”

Mechanisms of low-temperature rehabilitation technologies. Extreme aerocriotherapy

“…В то же время не менее доказательный экспериментальный материал демонстрирует обратное [40]. Есть основания предполагать, что экспрессия БТШ при гипотермии провоцируется не понижением температуры, а ее повышением в период согревания после охлаждения, и может происходить при значительно сниженных температурах [41,42]. Предполагают, что согревание после охлаждения активирует клеточное дыхание, кровоток и образование свободных радикалов в тканях, что формирует сигналы экспрессии ранних генов.…”