Investigation of the Protective Effects of Aripiprazole on Methylphenidate-induced Neurotoxicity in Rats

Methylphenidate (MPH) serves as a frequently utilized stimulant in the treatment of attention deficit hyperactivity disorder (ADHD). However, long-term administration of this medication has been linked to neurotoxic sequels such as cognitive decline and increased oxidative stress, especially in the hippocampus. In contrast, aripiprazole (ARP), an atypical antipsychotic, has shown promise in providing neuroprotection and reducing inflammation. This research seeks to investigate the protective role of ARP on MPH-induced neurotoxicity in rats. A total of 40 male Wistar rats participated in this study, which were organized into five groups. All the experimental groups received daily intraperitoneal injections of MPH at 10 mg/kg, combined with varying doses of ARP at 3, 10, and 30 mg/kg for 21 days. Behavioral assessments included the open field test and forced swimming test to evaluate motor activity and depressive-like behaviors, as well as the inhibitory avoidance test for cognitive function. Seizure susceptibility was assessed using pentylenetetrazol (PTZ). Following these evaluations, hippocampal tissues were collected for biochemical analysis (oxidative stress markers and neurotrophic factor) and histopathological studies. ARP at specific doses significantly mitigated locomotor activity impairment, depressive-like behaviors, and memory deficits induced by chronic MPH administration. Additionally, ARP reduced seizure susceptibility compared to the MPH-treated group. Biochemical analyses indicated that ARP decreased oxidative stress markers, including malondialdehyde (MDA) and myeloperoxidase (MPO), while enhancing levels of glutathione and the expression of brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (NRF2), and protein kinase B (Akt) in hippocampus. Aripiprazole reduces behavioral and biochemical deficits from chronic MPH use in rats, suggesting it may help mitigate adverse effects of long-term MPH treatment.