The Gliopeptide ODN, a Ligand for the Benzodiazepine Site of GABAA Receptors, Boosts Functional Recovery after Stroke.

Following stroke, the survival of neurons and their ability to reestablish 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 GABAA receptors (GABAARs). Conversely, in the late phase, negative allosteric modulation of GABAAR can correct the suboptimal excitability and improves both sensory and motor recovery. Here, we hypothesized that octadecaneuropeptide (ODN), an endogenous allosteric modulator of the GABAAR 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 makes 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 two different paradigms of experimental stroke in mice. Furthermore, we bring evidence that, during the subacute period after stroke, the repairing cortex can be treated with ODN by means of a single hydrogel deposit into the stroke cavity.SIGNIFICANCE STATEMENT Stroke remains a devastating clinical challenge because there is no efficient therapy to either minimize neuronal death with neuroprotective drugs or to enhance spontaneous recovery with neurorepair drugs. Around the brain damage, the peri-infarct cortex can be viewed as a reservoir of plasticity. However, the potential of wiring new circuits in these areas is restrained by a chronic excess of GABAergic inhibition. Here we show that an astrocyte-derived peptide, can be used as a delayed treatment, to safely correct cortical excitability and facilitate sensorimotor recovery after stroke.

Age-dependent Disturbances of Neuronal and Glial Protein Expression Profiles in Areas of Secondary Neurodegeneration Post-stroke.

Despite the fact that approximately 80% of strokes occur in those aged over 60 years, many pre-clinical stroke studies have been conducted in younger adult rodents, raising debate about translation and generalizability of these results. We were interested in potential age differences in stroke-induced secondary neurodegeneration (SND). SND involves the death of neurons in areas remote from, but connected to, the site of infarction, as well as glial disturbances. Here we investigated potential differences in key parameters of SND in the thalamus, a major site of post-stroke SND. Protein expression profiles in young adult (2-4 months) and aged (22-23 months) mice were analyzed 28 days after a cortical stroke. Our results show that age reduced the expression of synaptic markers (PSD 95, Synapsin1) and increased Amyloid ß oligomer accumulation after stroke. Protein expression of several markers of glial activity remained relatively stable across age groups post-stroke. We have identified that age exacerbates the severity of SND after stroke. Our results, however, do not support a view that microglia or astrocytes are the main contributors to the enhanced severity of SND in aged mice.

Dietary nitrate supplementation reduces low frequency blood pressure fluctuations in rats following distal middle cerebral artery occlusion.

It is known that high blood pressure variability (BPV) in acute ischemic stroke is associated with adverse outcomes, yet there are no therapeutic treatments to reduce BPV. Studies have found increasing nitric oxide (NO) bioavailability improves neurological function following stroke, but whether dietary nitrate supplementation could reduce BPV remains unknown. We investigated the effects of dietary nitrate supplementation on heart rate (HR), blood pressure (BP), and beat-to-beat BPV using wireless telemetry in a rat model of distal middle cerebral artery occlusion. Blood pressure variability was characterized by spectral power analysis in the low frequency (LF; 0.2-0.6 Hz) range prestroke and during the 7 days poststroke in a control group ( n = 8) and a treatment group ( n = 8, 183 mg/l sodium nitrate in drinking water). Dietary nitrate supplementation moderately reduced systolic BPV in the LF range by ~11% compared with the control group ( P = 0.03), while resting BP and HR were not different between the two groups ( P = 0.28 and 0.33, respectively). Despite systolic BPV being reduced with dietary nitrate, we found no difference in infarct volumes between the treatment and the control groups (1.59 vs. 1.62 mm3, P = 0.86). These findings indicate that dietary nitrate supplementation is effective in reducing systolic BPV following stroke without affecting absolute BP. In light of mounting evidence linking increased BPV with poor stroke patient outcome, our data support the role of dietary nitrate as an adjunct treatment following ischemic stroke. NEW & NOTEWORTHY Using a rat model of stroke, we found that dietary nitrate supplementation reduced low frequency blood pressure fluctuations following stroke without affecting absolute blood pressure values. Since blood pressure fluctuations are associated with poor clinical outcome in stroke patients, our findings indicate that dietary nitrate could be an effective strategy for reducing blood pressure fluctuations, which could help reduce stroke severity and improve patient recovery.