Mechanistic and therapeutic relationships of traumatic brain injury and γ-amino-butyric acid (GABA)

• Published in: Pharmacology & therapeutics (Oxford) 2024-04, Vol.256, p.108609-108609, Article 108609
• Main Authors: Witkin, Jeffrey M., Shafique, Hana, Cerne, Rok, Smith, Jodi L., Marini, Ann M., Lipsky, Robert H., Delery, Elizabeth
• Format: Article
• Language: English
• Subjects: Animal models; GABA; Glutamate; Post-traumatic epilepsy (PTE); Traumatic brain injury
• ISSN: 0163-7258; 1879-016X
• DOI: 10.1016/j.pharmthera.2024.108609

Traumatic brain injury (TBI) is a highly prevalent medical condition for which no medications specific for the prophylaxis or treatment of the condition as a whole exist. The spectrum of symptoms includes coma, headache, seizures, cognitive impairment, depression, and anxiety. Although it has been known for years that the inhibitory neurotransmitter γ-amino-butyric acid (GABA) is involved in TBI, no novel therapeutics based upon this mechanism have been introduced into clinical practice. We review the neuroanatomical, neurophysiological, neurochemical, and neuropharmacological relationships of GABA neurotransmission to TBI with a view toward new potential GABA-based medicines. The long-standing idea that excitatory and inhibitory (GABA and others) balances are disrupted by TBI is supported by the experimental data but has failed to invent novel methods of restoring this balance. The slow progress in advancing new treatments is due to the complexity of the disorder that encompasses multiple dynamically interacting biological processes including hemodynamic and metabolic systems, neurodegeneration and neurogenesis, major disruptions in neural networks and axons, frank brain lesions, and a multitude of symptoms that have differential neuronal and neurohormonal regulatory mechanisms. Although the current and ongoing clinical studies include GABAergic drugs, no novel GABA compounds are being explored. It is suggested that filling the gap in understanding the roles played by specific GABAA receptor configurations within specific neuronal circuits could help define new therapeutic approaches. Further research into the temporal and spatial delivery of GABA modulators should also be useful. Along with GABA modulation, research into the sequencing of GABA and non-GABA treatments will be needed.