Abstract
Obesity and diabetes mellitus have become the surprising menaces of relative economic well-being worldwide. Gamma amino butyric acid (GABA) has a prominent role in the control of blood glucose, energy homeostasis as well as food intake at several levels of regulation. The effects of GABA in the body are exerted through ionotropic GABAA and metabotropic GABAB receptors. This treatise will focus on the pharmacologic targeting of GABAA receptors to reap beneficial therapeutic effects in diabetes mellitus and obesity. A new crop of drugs selectively targeting GABAA receptors has been under investigation for efficacy in stroke recovery and cognitive deficits associated with schizophrenia. Although these trials have produced mixed outcomes the compounds are safe to use in humans. Preclinical evidence is summarized here to support the rationale of testing some of these compounds in diabetic patients receiving insulin in order to achieve better control of blood glucose levels and to combat the decline of cognitive performance. Potential therapeutic benefits could be achieved (i) By resetting the hypoglycemic counter-regulatory response; (ii) Through trophic actions on pancreatic islets, (iii) By the mobilization of antioxidant defence mechanisms in the brain. Furthermore, preclinical proof-of-concept work, as well as clinical trials that apply the novel GABAA compounds in eating disorders, e.g., olanzapine-induced weight-gain, also appear warranted.
Highlights
The effects of Gamma amino butyric acid (GABA) in the body are exerted through ionotropic (GABAA ) and metabotropic GABAB receptors [1,2,3]
Compounds such as diazepam or alprazolam, that enhance the effects of GABA by acting at the benzodiazepine site were referred to as agonists, while those that reduce the effect of GABA e.g., Ro15-4513 or DMCM were called inverse agonists
The optimal choice appears to be the combination of an α2-GABAA -R selective positive allosteric modulator (PAM) with a central nervous system (CNS)-penetrating α5 inhibitor (NAM or GABA antagonist)
Summary
The main site of GABA production is the central nervous system (CNS) where it is an abundant neurotransmitter. The biochemical synthetic, breakdown and uptake pathways for GABA are well known [4] Reuptake into both neurons and glial cells has been well characterized. Phasic GABAergic inhibition has been reported [11] Another significant category of GABA action is “tonic” inhibition, which is mediated by extra-synaptic GABAA -Rs [10]. Subsequent studies revealed that different GABAA receptor configurations underlie phasic and tonic effects of GABA [10,23,24]. These findings provided a strong biological rationale for the development of compounds selective for GABAA -R isoforms [22,25,26]
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