Long‐term morphological and functional evaluation of the neuroprotective effects of post‐ischemic treatment with melatonin in rats

Abstract

Consensus on neuroprotection has pointed out the relevance of the long-term morphological and functional evaluation of the effectiveness of putative neuroprotective procedures. In the present study, place learning (Morris water maze) and working memory (eight-arm Olton radial maze) were evaluated in adult male rats 90 days after 15 min of global cerebral ischemia (four-vessel occlusion) followed by continuous i.v. infusion (10 mg/kg/hr) of melatonin (Isch + Mel) or vehicle (Isch + Veh) for 6 hr, and the pyramidal neuron population of the cornus Ammoni (CA) of the hippocampus and layers III and V of the medial prefrontal cortex was assessed at the end of the behavioral testing period (120 days after ischemia). Impairment of place learning, a significant delay in working memory acquisition, and a significant loss of pyramidal neurons in the Ammon's horn (CA1: 23%, CA2: 52% CA3: 73%, hilus: 64% remaining neurons), were observed in the Isch + Veh group. By contrast, a similar performance of the Isch + Mel group to that in the Intact and Sham groups and better than that of the Isch + Veh group, besides a significant reduction of pyramidal neuron loss in the CA subfields (CA1: 79%, CA2: 88% CA3: 86%, hilus: 72% remaining neurons), documented that melatonin treatment led to a long-term preservation of both the neural substrate, and the capability for integration of spatial learning and memory, mainly dependent on a normal hippocampal functioning. Overall the results emphasize the efficacy of melatonin in counteracting the pathophysiological processes induced by ischemia, by exerting its actions during a short but critical period early after the ischemic episode.

Arylalkylamine N-acetyltransferase (AANAT) is expressed in astrocytes and melatonin treatment maintains AANAT in the gerbil hippocampus induced by transient cerebral ischemia

“…death in the hippocampus 5 days after ischemia/reperfusion. This result was supported by previous studies that melatonin protects brain damage from the ischemic damage in rats [30,31,[41][42][43][44] and gerbils [29].…”

Melatonin protects N2a against ischemia/reperfusion injury through autophagy enhancement

“…# Corresponding author, E-mail: duanqhwz@hotmail.com * This project was supported by a grant from the PhD Programs Experimental data from numerous studies clearly showed that melatonin, a biogenic amine produced by the pineal gland, is a highly effective agent in reducing neuronal loss and neurophysiologic deficits associated with brain ischemia and reperfusion (I/R) both in animal models and at cell level [7][8][9][10][11][12] . Yet the real mechanism for this neuronal protection is not fully elucidated.…”

Neuroprotection in Animal Models of Global Cerebral Ischemia

“…Methylene blue Wiklund et al, 2007. Melatonin Cervantes et al, 2008Cho et al, 1997;El-Abhar et al, 2002;García-Chávez et al, 2008;González-Burgos et al, 2007;Letechipía-Vallejo et al, 2001;Letechipía-Vallejo et al, 2007;Rennie et al, 2008;Weil et al, 2009. Other Bashkatova et al, 2001Fang et al, 2010;Gaur & Kumar, 2010;Nanri et al, 1998;Pazos et al, 1999;Sinha et al, 2001;Warner et al, 2004.…”

“…Thus, pyramidal neuron population in the Ammon´s horn of the hippocampus and in the neocortex (Bleayert et al, 1978;Colbourne & Corbett, 1994;García-Chávez et al, 2008;Hartman et al, 2005;Johansen & Diemer, 1991;Kirino, 1982;Letechipía-Vallejo et al, 2007;Moralí et al, 2011b;Pulsinelli, 1985;Schmidt-Kastner & Freund, 1991;, or different neuron types in other brain vulnerable structures (Block & Schwartz, 1998;Cervantes et al, 2002), have been evaluated through the number and proportion of surviving neurons. However, most of these studies deal with histopathological assessment of the hippocampus, the highest vulnerable brain region to global cerebral ischemia.…”