Apelin-13 confers Neuropeptide Y–mediated neuroprotection and preserves learning and allocentric memory in D-glutamic acid-induced excitotoxicity in rats

Glutamate-mediated excitotoxicity causes mitochondrial dysfunction, apoptosis, neuronal death. Aim of this study is to investigate whether Apelin-13, together with NPY2 and NPY5 receptors, plays a cooperative role in neuroprotection and in preventing learning and memory impairments under excitotoxic conditions. D-Glutamic acid-induced excitotoxicity was established in 42-male Sprague-Dawley rats (6-8 weeks, 200-250g). Animals were randomly divided into six-groups(n=7); Control (C; 0.9% NaCl, i.p), D-Glutamic Acid (G; 4 mg/kg, i.p), Apelin-13 (A; 300 µg/kg, i.p), D-Glutamic Acid+Apelin-13 (GA), GA+NPY2 receptor(NPY2R) antagonist (GAN2; 1,5 mg/kg, i.p) and GA+NPY5 receptor(NPY5R) antagonist (GAN5; 1,5 mg/kg, i.p). Short-long term memory, learning performance, allocentric-egocentric orientation, locomotor activity were evaluated with Open field (OFT), novel object recognition (NORT), Morris water maze (MWM) tests. In group G, there was an increase in Caspase-3 level(p<0.001), while significant decrease (p<0.001) was observed in Extracellular Signal Regulatory Kinase (ERK1/2) and Protein Kinase B-1(AKT-1) levels. Increased mitochondrial dysfunction indicated neurodegeneration due to excitotoxicity. In MWM an increase latency to the target quadrant (p<0.001), a decrease in the NORT discrimination index (p<0.001) were found. Apelin-13 was observed to have a neuroprotective role by alleviating the damage in GA group. While the protective effect of Apelin-13 was not observed in the presence of NPY2R antagonist; when NPY5R antagonist was applied, more pronounced neuroprotection was detected in GAN5 group compared to GAN2, since NPY2R activity continued. Histochemical staining-scorings showed that protection of Apelin-13 was mediated by NPY2R. Apelin-13 exerts its neuroprotective effects primarily through NPY2R, its modulatory influence via NPY5R appears to be comparatively limited.