The gliopeptide ODN, a ligand for the benzodiazepine site of GABA_Areceptors, boosts functional recovery after stroke

Abstract

Following stroke, the survival of neurons and their ability to re-establish connections is critical to functional recovery. This is strongly influenced by the balance between neuronal excitation and inhibition. In the acute phase of experimental stroke, lethal hyperexcitability can be attenuated by positive allosteric modulation of GABA A receptors (GABA A R). Conversely, in the late phase, negative allosteric modulation of GABA A R can correct the sub-optimal excitability and improves both sensory and motor recovery. Here, we hypothesized that octadecaneuropeptide (ODN), an endogenous allosteric modulator of the GABA A R synthesized by astrocytes, influences the outcome of ischemic brain tissue and subsequent functional recovery. We show that ODN boosts the excitability of cortical neurons, which make it deleterious in the acute phase of stroke. However, if delivered after day 3, ODN is safe and improves motor recovery over the following month in both young and aged mice. Furthermore, we bring evidence that during the sub-acute period after stroke, the repairing cortex can be treated with ODN by means of a single hydrogel deposit into the stroke cavity.

Brain oscillatory modes as a proxy of stroke recovery

“…Immediately after stroke, during the hyperacute phase, hyperinhibition of the perilesional cortical areas prevents additional tissue damage due to ischemia-induced excitotoxicity (80)(81)(82). However, the persistence of hyperinhibition over time was correlated with worse motor outcomes (27,28), and pharmacological reduction in GABAergic inhibition led to better recovery in animal models (27,83,84). Further evidence has confirmed this last point by linking better motor recovery with a period of plasticity driven by molecular changes, such as cellular excitability (85), or by sustained disinhibition during the first weeks poststroke.…”

Cytoprotective and Neurotrophic Effects of Octadecaneuropeptide (ODN) in in vitro and in vivo Models of Neurodegenerative Diseases

“…Altogether, these results demonstrate that, based on its antioxidative ( 77 , 82 ), anti-inflammatory ( 35 ), and antiapoptotic effects ( 63 , 71 ), the gliopeptide ODN, which acts as a potent neuroprotective agent, could lead to the development of effective therapeutic agents for the treatment of cerebral injuries involving oxidative neurodegeneration. It should nevertheless be pointed out that in the acute phase of stroke, ODN, through its allosteric modulation of GABA A receptor, boosts the excitability of cortical neurons and as a consequence increases neuronal damages ( 83 ). Consistent with this observation, DBI −/− mice exhibit increased infarct volume compared to wild-type animals.…”