Experimental models for preclinical investigations of novel drugs for traumatic brain injury = Pirmsklīnisko pētījumu eksperimentālie modeļi galvas traumu pētījumiem ar jaunām zāļu vielām

Abstract

Traumatic brain injury (TBI) is one of the leading causes of trauma-related permanent disability in humans and small animals (dogs, cats). TBI in humans and small animals can result in temporary, long-term, and even life-long physical, cognitive, and behavioral problems. Currently, no effective treatment is available for TBI-induced deficits other than supportive therapy in humane and veterinary medicine. Therefore, there is an increased need for effective pharmacological approaches for treating patients with TBI. Animal models are necessary to gain a deeper insight into the events that follow a TBI, and ultimately apply the findings to the clinical setting. The aim of this thesis was to improve experimental models of TBI and find potential novel drug targets for the treatment or delay of TBI-induced neurological impairments. Animals experiencing skull fractures after being subjected to the wight drop model showed a substantial inflammatory response in the brain, while animals without skull fractures did not, thus demonstrating how skull fractures contribute to the heterogeneity of the WD model. Moderate lateral fluid percussion injury (latFPI) in mice elicits long-lasting impairment of sensory-motor function, results in progressive depression and potentiates peripheral pain. R-phenibut treatment reduces TBI-induced neuronal death and improves functional recovery, suggesting its therapeutic potential. The present study suggests that the neuroprotective properties of R-phenibut may be mediated by its effects on mitochondrial calcium influx and reactive oxygen species (ROS) generation. Sigma-1 receptor (S1R) deficiency led to improved neurological and motor coordination, reduced despair-like behavior, preserved long-term cognitive function, and prevented latFPI-induced neuroinflammation 12 months postinjury. S1R deficiency was associated with reduced GFAP expression in Bergmann glial cells in the cerebellum. These findings suggest a role for S1R in the pathogenesis of TBI and cerebellum-mediated motor behavior. The thesis is presented as a unifying material of peer-reviewed publications, and it summarizes the study materials and results of the evaluations of the preclinical models of TBI. The results show that the latFPI model provides a relevant preclinical setting for the study of the link between brain injury and chronic sequelae such as depression and peripheral pain. As well, S1R is a potential novel target for TBI-related treatments.