Donat Cornelius K, Fischer Felix, Walter Bernd, Deuther-Conrad Winnie, Brodhun Michael, Bauer Reinhard, Brust Peter
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, Leipzig, Germany,
Acta Neurobiol Exp (Wars). 2014;74(2):197-210. doi: 10.55782/ane-2014-1985.
Paediatric traumatic brain injury (TBI) is a leading cause of death and disability. Previous studies showed neuroprotection after TBI by (endo)cannabinoid mechanisms, suggesting involvement of cannabinoid receptors (CBR). We therefore determined CBR densities and expression of the translocator protein 18 kDA (TSPO) in newborn piglets after experimental TBI. Newborn female piglets were subjected to sham operation (n=6) or fluid-percussion (FP) injury (n=7) under controlled physiological conditions. After six hours, brains were frozen, sagittally cut and incubated with radioligands for CBR ([3HCP-55,940, [3H]SR141716A) and TSPO ([3H]PK11195), an indicator of gliosis/brain injury. Early after injury, FP-TBI elicited a significant ICP increase at a temporary reduced cerebral perfusion pressure; however, CBF and CMRO2 remained within physiological range. At 6 hours post injury, we found a statistically significant increase in binding of the non-selective agonist [3H]CP-55,940 in 15 of the 24 investigated brain regions of injured animals. By contrast, no significant changes in binding of the CB1R-selective antagonist [3H]SR141716A were observed. A non-significant trend towards increased binding of [3H]PK11195 was observed, suggesting an incipient microglial activation. We therefore conclude that in this model and time span after injury, the increase in [3H]CP-55,940 binding reflects changes in CB2R density, while CB1R density is not affected. The results may provide explanation for the neuroprotective properties of cannabinoid ligands and future therapeutic strategies of TBI.
小儿创伤性脑损伤（TBI）是死亡和残疾的主要原因。先前的研究表明，（内源性）大麻素机制可在TBI后起到神经保护作用，提示大麻素受体（CBR）参与其中。因此，我们测定了实验性TBI后新生仔猪体内CBR的密度以及18 kDa转位蛋白（TSPO）的表达。在可控的生理条件下，对新生雌性仔猪进行假手术（n = 6）或液压冲击（FP）损伤（n = 7）。6小时后，将大脑冷冻，矢状切开，并用放射性配体[3H]CP-55,940、[3H]SR141716A（用于CBR）和[3H]PK11195（用于TSPO，为神经胶质增生/脑损伤的指标）进行孵育。损伤后早期，FP-TBI导致颅内压显著升高，同时脑灌注压暂时降低；然而，脑血流量（CBF）和脑氧代谢率（CMRO2）仍保持在生理范围内。损伤后6小时，我们发现，在受伤动物的24个被研究脑区中的15个区域，非选择性激动剂[3H]CP-55,940的结合有统计学意义的增加。相比之下，未观察到CB1R选择性拮抗剂[3H]SR141716A的结合有显著变化。观察到[3H]PK11195的结合有增加的非显著趋势，提示小胶质细胞开始激活。因此，我们得出结论，在该模型及损伤后的这段时间内，[3H]CP-55,940结合的增加反映了CB2R密度的变化，而CB1R密度未受影响。这些结果可能为大麻素配体的神经保护特性及未来TBI的治疗策略提供解释。
