Galantamine Postischemia Provides Neuroprotection and Memory Recovery against Transient Global Cerebral Ischemia in Gerbils

Abstract

Galantamine, currently used in Alzheimer's patients, has shown neuroprotection in hippocampal slices subjected to oxygenglucose deprivation. Here, we present an in vivo study to evaluate the potential neuroprotective effects of galantamine in a transient global cerebral ischemia model in gerbils. Three treatment protocols were used. In the pretreatment protocol, gerbils were treated before ischemia and for 3 consecutive days thereafter. Eight groups of animals were included: sham operation plus placebo, 10 mg/kg mecamylamine and 10 mg/kg galantamine, respectively; and ischemia plus placebo, 10 mg/kg mecamylamine, 1 mg/kg galantamine, and 10 mg/kg galantamine and 10 mg/kg mecamylamine plus galantamine, respectively. Postischemia protocols included three groups of animals: sham operation, ischemia plus placebo, and ischemia plus 10 mg/kg galantamine; substances were administered 3 or 6 h after ischemia and for 2 consecutive days thereafter. Pyramidal neurons surviving in the cornus ammonis 1 region of the hippocampus were evaluated 72 h after reperfusion, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) histochemistry, caspase-3 and superoxide dismutase (SOD)-2 immunohistochemistries, and Western blottings were performed, and object placement tests were carried out. Galantamine significantly increased the number of living pyramidal neurons after ischemia-reperfusion injury. Galantamine significantly reduced TUNEL, active caspase-3, and SOD-2 immunoreactivity. The nicotinic antagonist mecamylamine blocked the protective effects of galantamine. The neuroprotective effects of galantamine were preserved even when first administered at 3 h postischemia. These results correlated with the performance in the object placement test. This study shows that galantamine provides in vivo neuroprotection and memory recovery against global cerebral ischemia, even when administration begins 3 h postischemia.

Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment

“…Moreover, a post-ischemic single administration of galantamine also showed a beneficial effect on the recovery of learning ability in rats [116] , which suggests a direct effect of galantamine on the early pathologic changes of CNS damage. In addition, continuous administration of galantamine could protect pyramidal neurons in the hippocampal CA1 region of ischemic gerbils and lead to the recovery of spatial memory in a transient brain global ischemic model in gerbils [117,118] . Furthermore, galantamine attenuated the release of cytokines from activated murine microglia [119] .…”

Neuroprotection of Ischemic Preconditioning is Mediated by Anti-inflammatory, Not Pro-inflammatory, Cytokines in the Gerbil Hippocampus Induced by a Subsequent Lethal Transient Cerebral Ischemia

“…This is known as ''selective vulnerability'' in the brain induced by lethal transient ischemic insult [24]. Mongolian gerbils that have been used as an excellent animal to study mechanisms of selective neuronal death following transient global cerebral ischemia [25,26], because about 90 % of the gerbils lack the communicating vessels between the carotid and vertebral circulations [27,28]. We found a significant loss of pyramidal neurons in stratum pyramidale of the ischemic CA1 region in the ischemia-groups 5 days after ischemia-reperfusion using NeuN immunohistochemistry and F-J B histofluorescence staining.…”

Subthreshold Concentrations of Melatonin and Galantamine Improves Pathological AD-Hallmarks in Hippocampal Organotypic Cultures

“…5a, b). Because we had previously shown that galantamine's neuroprotective actions were mediated by α7 nAChR [28,29], we used α-bungarotoxin (a selective α7 nAChR antagonist) and luzindole (a melatonin receptor antagonist) to evaluate if these receptors were participating in the neuroprotective actions of Gal/Mel. Indeed, both α-bungarotoxin and luzindole (which did not afford any cell viability modification per se, data not shown) prevented the reduction of Il-1β and TNF-α mRNA levels caused by Gal/Mel in OHCs incubated with βA/OA (Fig.…”

“…The culture media consisted of 50 % minimal essential medium (MEM), 25 % Hank's balanced salt solution, and 25 % heat-inactivated horse serum (Life Technologies, Madrid, Spain). After 4 days in culture, OHCs were treated with β-amiloyd [25][26][27][28][29][30][31][32][33][34][35] (βA, Sigma-Aldrich, Spain), okadaic acid (OA, Tocrisscientific/Biogen, Madrid, Spain), or the association of both toxic stimuli for 4 days, in the absence or presence of the protective drugs (melatonin, galantamine). OHCs were cultured in a humidified atmosphere at 37°C and 5 % CO 2 , and the medium was changed twice a week.…”