Prolonged Therapeutic Hypothermia does not Adversely Impact Neuroplasticity after Global Ischemia in Rats

Abstract

Hypothermia improves clinical outcome after cardiac arrest in adults. Animal data show that a day or more of cooling optimally reduces edema and tissue injury after cerebral ischemia, especially after longer intervention delays. Lengthy treatments, however, may inhibit repair processes (e.g., synaptogenesis). Thus, we evaluated whether unilateral brain hypothermia (∼33°C) affects neuroplasticity in the rat 2-vessel occlusion model. In the first experiment, we cooled starting 1 hour after ischemia for 2, 4, or 7 days. Another group was cooled for 2 days starting 48 hours after ischemia. One group remained normothermic throughout. All hypothermia treatments started 1 hour after ischemia equally reduced hippocampal CA1 injury in the cooled hemisphere compared with the normothermic side and the normothermic group. Cooling only on days 3 and 4 was not beneficial. Importantly, no treatment influenced neurogenesis (Ki67/Doublecortin (DCX) staining), synapse formation (synaptophysin), or brain-derived neurotropic factor (BDNF) immunohistochemistry. A second experiment confirmed that BDNF levels (ELISA) were equivalent in normothermic and 7-day cooled rats. Last, we measured zinc (Zn), which is important in plasticity, with X-ray fluorescence imaging in normothermic and 7-day cooled rats. Hypothermia did not alter the postischemic distribution of Zn within the hippocampus. In summary, cooling significantly mitigates injury without compromising neuroplasticity.

Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion

“…Thrombolysis is the only approved method for stroke therapy (41), but it can be applied to less than 10% of the patients due to the stringent treatment criteria (26) and in some cases may even produce further reperfusion injury (2). Mild hypothermia (32-34°C) has been demonstrated to reduce stroke injury and improve neurofunctional recovery in animal studies and has shown promise in small-scale clinical trials (20,25,37,49,50). At present, most clinical therapeutic hypothermia (TH) protocols involve methods of forced cooling such as with cold blankets and ice baths or intravenous methods of cooling (25).…”

Laminar-specific distribution of zinc: Evidence for presence of layer IV in forelimb motor cortex in the rat

“…A tightly controlled and well validated sample preparation protocol (Hackett et al, 2012a; Silasi et al, 2012) was employed in this study to avoid the potential confounding effects associated with other techniques that stain the labile Zn pool. As described above, great variation is often observed between independent studies of the labile Zn distribution (Frederickson et al, 2000; Perez-Clausell, 1996).…”

Therapeutic hypothermia for stroke: Where to go?

“…A few experimental studies have demonstrated the beneficial effects of hypothermia on promoting neurogenesis after ischemia (Silasi and Colbourne, 2011;Silasi et al, 2012;Xiong et al, 2011). Although scientific literature regarding the role of hypothermia in neuronal connectivity repair after ischemia is scarce, it was proved that hypothermia would enhance neurite outgrowth in vitro, and upregulate genes involved in synapse organization in rat models of traumatic brain injury (Feng et al, 2010;Schmitt et al, 2010).…”