Altered neuronal Ca²⁺ homeostasis and mitochondrial dysfunction play a central role in the pathogenesis of traumatic brain injury (TBI). R-Phenibut ((3R)-phenyl-4-aminobutyric acid) is an antagonist of the α₂δ subunit of voltage-dependent calcium channels (VDCC) and an agonist of gamma-aminobutyric acid B (GABA-B) receptors. The aim of this study was to evaluate the potential therapeutic effects of R-phenibut following the lateral fluid percussion injury (latFPI) model of TBI in mice and the impact of R- and S-phenibut on mitochondrial functionality in vitro. By determining the bioavailability of R-phenibut in the mouse brain tissue and plasma, we found that R-phenibut (50 mg/kg) reached the brain tissue 15 min after intraperitoneal (i.p.) and peroral (p.o.) injections. The maximal concentration of R-phenibut in the brain tissues was 0.6 μg/g and 0.2 μg/g tissue after i.p. and p.o. administration, respectively. Male Swiss-Webster mice received i.p. injections of R-phenibut at doses of 10 or 50 mg/kg 2 h after TBI and then once daily for 7 days. R-Phenibut treatment at the dose of 50 mg/kg significantly ameliorated functional deficits after TBI on postinjury days 1, 4, and 7. Seven days after TBI, the number of Nissl-stained dark neurons (N-DNs) and interleukin-1beta (IL-1β) expression in the cerebral neocortex in the area of cortical impact were reduced. Moreover, the addition of R- and S-phenibut at a concentration of 0.5 μg/ml inhibited calcium-induced mitochondrial swelling in the brain homogenate and prevented anoxia-reoxygenation-induced increases in mitochondrial H₂O₂ production and the H₂O₂/O ratio. Taken together, these results suggest that R-phenibut could serve as a neuroprotective agent and promising drug candidate for treating TBI.

中文翻译：

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实验性颅脑外伤后R-苯丙氨酸的线粒体保护作用

神经元Ca ²⁺稳态的改变和线粒体功能障碍在创伤性脑损伤（TBI）的发病机理中起着核心作用。R-Phenibut（（3R） -苯基- 4-氨基丁酸）是拮抗剂的α ₂ δ电压依赖性钙通道（VDCC）和γ-氨基丁酸B（GABA-B）受体的激动剂的亚基。这项研究的目的是评估在小鼠TBI的侧向液体敲击损伤（latFPI）模型后R-苯乙但是可能的治疗作用以及R-和S-苯但对体外线粒体功能的影响。通过确定小鼠脑组织和血浆中的R-phenibut生物利用度，我们发现腹膜内（ip）和经口（po）注射15分钟后R-phenibut（50 mg / kg）到达了脑组织。R-phenibut在脑组织的最大浓度为0.6  μ克/克和0.2  μ克/克组织ip和po施用，分别之后。雄性Swiss-Webster小鼠在TBI后2 h腹腔注射R-phenibut，剂量为10或50 mg / kg，然后每天一次，共7天。R-Phenibut治疗剂量为50 mg / kg可以明显减轻损伤后第1、4和7天TBI后的功能缺陷。TBI后第7天，Nissl染色的黑暗神经元（N-DNs）和白介素1beta的数量（IL- 1β）在大脑新皮层的表达受到皮层影响的程度降低。此外，添加R-和S- phenibut的以0.5:1的浓度 μ克/ ml，在线粒体ħ抑制钙诱导的线粒体在脑匀浆肿胀和防止缺氧复氧诱导的增加₂ ö ₂生产和H ₂ ö ₂ / O比。综上所述，这些结果表明，R-苯丁醚可以作为神经保护剂和有望用于治疗TBI的候选药物。