How does a Benzodiazepine produce a transient awakening of patients under severe long-lasting comatose state due to heavy brain lesions ?

Awakening, a temporary revival of patients who have been akinetic, apathic and with no reaction for years following a large brain damage, has been observed after administration of drugs, but the mechanisms underlying them remain unknown. In a recent study, Arnst et al. report spectacular effects of Zolpidem on a 29 years old patient after a severe hypoxic-ischemic brain injury with signs of diffuse brain atrophy. For 8 years the patient remained mute, akinetic, apathic, incontinent, with muscle rigidity and no affective reactions. Following a single dose of Zolpidem (10 mg), the patient “managed to walk while being supported by the staff and phoned his father, who had not heard his son’s voice for years. Despite evident retrograde amnesia, going back three years before the brain injury, and an apparent hearing deficit, he was cheerful, alert, and showing interest in the people and objects surrounding him”.  However, the underlying mechanisms for this awakening effect remain unknown.

Benzodiazepines such as Zolpidem enhance the efficacy of the inhibitory transmitter GABA, hence its classic anesthetic and anxiolytic actions. Extensive experimental work suggests that GABA excites neurons instead of inhibiting them after brain damage and a large variety of cerebral disorders. In my recent publication in Translational Medicine Communications ( I propose that the “paradoxical” actions of Benzodiazepines are therefore due to the enhancement of the now excitatory GABA. These alterations are produced by a shift of the polarity of the actions of GABA due to an increase of intracellular chloride concentration ([Cl]i) levels. Indeed, the polarity of GABA actions is tightly correlated to these levels: being inhibitory when [Cl]i is low and exerting often excitatory actions when it is elevated. There are reports of paradoxical actions of Benzodiazepines after severe recurrent seizures or other insults. In fact, there are good reasons to believe that the paradoxical actions of Benzodiazepines are a good biomarker of elevated [Cl]i levels. There are also other conditions -notably autism and Parkinson’s disease- where the disorder can be attenuated by agents capable of restoring low [Cl]i levels. The [Cl]i levels are controlled by 2 proteins one enhancing its import and accumulation (NKCC1) and the other exporting it and thus reducing its levels (KCC2). Bumetanide, a highly selective antagonist of NKCC1, has shown a high degree of efficacy in reducing [Cl]i levels and attenuating the severity of autism in children and also in experimental conditions of brain damage produced by trauma. In addition, it has been shown that a co-administration of Bumetanide and a Benzodiazepine enhances the efficacy of the latter. Therefore, it is likely that the administration of Bumetanide alone or in conjunction with a Benzodiazepine will augment the efficacy and duration of awakening. As the side effects of Bumetanide are well described and readily controlled, this hypothesis can be tested.

Yehezkel Ben-Ari CEO Neurochlore

Reference :

  • Y. Ben-Ari. Is the awakening produced by benzodiazepines due to excitatory actions of GABA? Translational Medicine Communications 2021:6:6