Are GABAergic drugs beneficial in providing neuroprotection after traumatic brain injuries? A comprehensive literature review of preclinical studies

Abstract

Traumatic brain injuries (TBI) caused by physical impact to the brain can adversely impact the welfare and well-being of the affected individuals. One of the leading causes of mortality and dysfunction in the world, TBI is a major public health problem facing the human community. Drugs that target GABAergic neurotransmission are commonly used for sedation in clinical TBI yet their potential to cause neuroprotection is unclear. In this paper, I have performed a rigorous literature review of the neuroprotective effects of drugs that increase GABAergic currents based on the results reported in preclinical literature. The drugs covered in this review include the following: propofol, benzodiazepines, barbiturates, isoflurane, and other drugs that are agonists of GABAA receptors. A careful review of numerous preclinical studies reveals that these drugs fail to produce any neuroprotection after a primary impact to the brain. In numerous circumstances, they could be detrimental to neuroprotection by increasing the size of the contusional brain tissue and by severely interfering with behavioral and functional recovery. Therefore, anesthetic agents that work by enhancing the effect of neurotransmitter GABA should be administered with caution of TBI patients until a clear and concrete picture of their neuroprotective efficacy emerges in the clinical literature.

Exploring Comorbidity Networks in Mild Traumatic Brain Injury Subjects through Graph Theory: A Traumatic Brain Injury Model Systems Study

“…Unfortunately, despite the concerted efforts by the TBI community in search of a potential therapeutic agent to prevent the cascade of secondary brain injuries, no clinical trials have been successful so far on humans (Bullock et al 1999;Xiong et al 2009;Stein 2015;Sudhakar et al 2019;Sudhakar 2023). Even though numerous drugs have shown superior efficacy in preventing secondary injuries in animal models of TBIs, such an effect was not seen in human clinical trials (Bullock et al 1999;Stein 2015).…”

“…On the other hand, the pathophysiological mechanisms guiding the development and subsequent spread of secondary brain injuries could be halted by applying numerous therapeutic strategies (Werner and Engelhard 2007; Algattas and Huang 2013; Prins et al 2013). Unfortunately, despite the concerted efforts by the TBI community in search of a potential therapeutic agent to prevent the cascade of secondary brain injuries, no clinical trials have been successful so far on humans (Bullock et al 1999; Xiong et al 2009; Stein 2015; Sudhakar et al 2019; Sudhakar 2023). Even though numerous drugs have shown superior efficacy in preventing secondary injuries in animal models of TBIs, such an effect was not seen in human clinical trials (Bullock et al 1999; Stein 2015).…”

Prevalence of comorbidities post mild traumatic brain injuries: a traumatic brain injury model systems study

“…As a result, TBI and associated comorbidities could impose a severe financial burden on both the patient population and governments worldwide ( Gururaj, 2002 ; Langlois et al, 2006 ; Kayani et al, 2009 ; Lee et al, 2021 ). Furthermore, numerous clinical trials to find a cure for TBI have failed to produce the desired benefit in the patient population ( Ye et al, 2009 ; Stein, 2015 ; Sudhakar et al, 2019 ; Sudhakar, 2023 ). Existing treatment options focus on preventing secondary brain damage through careful clinical management of patients ( Jacobi et al, 2002 ; Armitage-Chan et al, 2007 ; Flower and Hellings, 2012 ; Vella et al, 2017 ; Dash and Chavali, 2018 ; Ripley et al, 2019 ).…”

“…Heterogeneity is also widespread in mild TBI where distinct clusters of the patient population were reported across multiple datasets based on demographics, injury-related information, and laboratory metrics ( Si et al, 2018a , b ; Pugh et al, 2021 ). In addition to an incomplete understanding of the activation of cellular and molecular cascades post mild TBI ( Werner and Engelhard, 2007 ; Schwab et al, 2022 ), the presence of widespread heterogeneity ( Saatman et al, 2008 ; Maas, 2016 ; Si et al, 2018a , b ) has made it quite challenging to come up with a drug to stop secondary brain injuries from happening ( Ye et al, 2009 ) resulting in low success rates of numerous clinical trials ( Ye et al, 2009 ; Stein, 2015 ; Sudhakar, 2023 ). When effective therapeutic options become limited for TBI, properly planned patient care ( Vella et al, 2017 ; Dash and Chavali, 2018 ) along with proactive disease prevention measures could vastly improve patient experiences.…”