Abstract
Stroke affects millions of people worldwide each year, and stroke survivors are often left with motor deficits. Current therapies to improve these functional deficits are limited, making it a priority to better understand the pathophysiology of stroke recovery and find novel adjuvant options. The excitation–inhibition balance undergoes significant changes post-stroke, and the inhibitory neurotransmitter γ-aminobutyric acid (GABA) appears to play an important role in stroke recovery. In this review, we summarise the most recent studies investigating GABAergic inhibition at different stages of stroke. We discuss the proposed role of GABA in counteracting glutamate-mediated excitotoxicity in hyperacute stroke as well as the evidence linking decreased GABAergic inhibition to increased neuronal plasticity in early stroke. Then, we discuss two types of interventions that aim to modulate the excitation–inhibition balance to improve functional outcomes in stroke survivors: non-invasive brain stimulation (NIBS) and pharmacological interventions. Finding the optimal NIBS administration or adjuvant pharmacological therapies would represent an important contribution to the currently scarce therapy options.
Highlights
Ten million people worldwide have a stroke each year[1], making stroke a leading cause of both morbidity and mortality[2,3], with survivors often left with motor impairments that limit their independence[1,4]
The gold standard interventions for motor rehabilitation are limited to physical/ occupational therapies: patients are given task-specific training[11], which focuses on gaining new motor skills, constraint-induced movement therapy (CIMT)[12], or robotic therapy[13,14]
It is difficult to explain why during early stroke patients seem to have both a lower excitation–inhibition ratio and lower intracortical inhibition, especially since there are no significant differences in transcranial magnetic stimulation (TMS)- or magnetic resonance spectroscopy (MRS)-derived metrics of glutamate activity
Summary
Ten million people worldwide have a stroke each year[1], making stroke a leading cause of both morbidity and mortality[2,3], with survivors often left with motor impairments that limit their independence[1,4]. Chronic stroke Chronic stroke patients are unlikely to improve their motor function after approximately 6 months post-stroke unless given rehabilitation, suggesting that the neurochemical milieu is significantly different in this period compared to in early stroke Characterising this has proved difficult: the majority of studies in humans occur in the chronic phase, there is a paucity of data from animal models regarding excitation–inhibition balance. Reducing pathologically increased tonic inhibition with S44819 during early stroke led to better motor function in mice[78], with associated increased neuronal viability, decreased peri-infarct astrogliosis, increased brain capillary density, and higher proliferation of neural precursor cells Despite this promising evidence from preclinical studies, a recent phase II clinical trial reported no significant difference in overall post-stroke recovery after long-term administration of S44819 in early stroke compared with placebo[79]. Improving translation can be achieved only by understanding the limitations of animal models of stroke, finding appropriate outcome measurements that can be compared between humans and animals, and designing preclinical and clinical experiments that can be compared in terms of dose and time of drug administration
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