Neurotoxic effects of pregabalin dependence on the brain frontal cortex in adult male albino rats.

Pregabalin (PGB) is an analog of the inhibitory neurotransmitter gamma-aminobutyric acid. The currently available evidence favors the misuse and abuse potential of PGB. However, its neurotoxicity remains unclear. Therefore, this study assessed the toxic effects of chronic pregabalin dependence as well as withdrawal on the cortical neurons of the frontal lobe. This study included eighty adult male albino rats which were divided into three groups. Group I (Control) included 40 rats and was further subdivided into two equal subgroups (IA and IB) as negative and positive controls. Group II (PGB-dependent) included 20 rats which received PGB starting with the therapeutic dose (300 mg/day), then the doses were gradually increased until they reached the dependent dose (3400 mg/day) by the end of the first month. Further, the dependent dose was given daily for another 2 months. Group III (PGB withdrawal) included 20 rats which received PGB as described in group II. After that, administration of PGB was stopped and the rats were kept for another one month. By the end of the experiment, all animals were sacrificed by cervical decapitation. The specimens were taken from the frontal cortex for histologic and immunohistochemical staining as well as morphometric analysis. Sections of the frontal cortex of group II showed changes in the form of disturbed architectural pattern of cortical layers, apoptotic cells, weak immunoexpression of Bcl-2 and VEGF as well as moderate-strong immunoexpression of iNOS and nestin. These expressions were significantly different from the control groups, but they were non-significant in comparison with group III. These findings indicate that chronic PGB dependence induces neurotoxic effects mainly in the form of neuronal apoptosis, gliosis, and oxidative stress injury of the frontal cortex. The PGB- induced neurotoxic effects persisted after withdrawal. The influence of these neurotoxic effects and their relevance to the cognitive or neurologic disorders in PGB-dependent individuals warrants further research. Furthermore, it is recommended to quantify the behavioral changes related to PGB dependence as well as withdrawal in future studies.