Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
Anatomy and Embryology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
Neurotoxicology. 2021 Mar;83:146-155. doi: 10.1016/j.neuro.2021.01.004. Epub 2021 Jan 27.
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.
普瑞巴林（PGB）是抑制性神经递质γ-氨基丁酸的类似物。目前的证据表明，PGB 具有滥用和误用的潜力。然而，其神经毒性尚不清楚。因此，本研究评估了慢性 PGB 依赖及戒断对额叶皮质神经元的毒性作用。
本研究包括 80 只成年雄性白化大鼠，分为三组。第 I 组（对照组）包括 40 只大鼠，进一步分为两个相等的亚组（IA 和 IB），作为阴性和阳性对照。第 II 组（PGB 依赖组）包括 20 只大鼠，从治疗剂量（300mg/天）开始接受 PGB，然后剂量逐渐增加，直到第一个月结束时达到依赖剂量（3400mg/天）。此外，依赖剂量每天给予另 2 个月。第 III 组（PGB 戒断组）包括 20 只接受如第 II 组所述的 PGB 的大鼠。之后，停止给予 PGB，大鼠再保持一个月。实验结束时，所有动物均经颈脱位处死。从额叶皮质取标本进行组织学和免疫组织化学染色以及形态计量学分析。第 II 组的额叶皮质切片显示皮质层结构模式紊乱、凋亡细胞、Bcl-2 和 VEGF 免疫表达减弱以及 iNOS 和巢蛋白免疫表达中度至强等改变。这些表达与对照组相比有显著差异，但与第 III 组相比无显著差异。
这些发现表明，慢性 PGB 依赖主要以神经元凋亡、神经胶质增生和额叶皮质氧化应激损伤的形式诱导神经毒性作用。PGB 诱导的神经毒性作用在戒断后仍然存在。这些神经毒性作用的影响及其与 PGB 依赖个体认知或神经障碍的相关性需要进一步研究。此外，建议在未来的研究中定量评估与 PGB 依赖及戒断相关的行为变化。
