Long-term chemogenetic activation of M1 glutamatergic neurons attenuates the behavioral and cognitive deficits caused by intracerebral hemorrhage.

Acute spontaneous intracerebral hemorrhage (ICH) is a life-threatening disease. It is often accompanied by severe neurological sequelae largely caused by the loss of integrity of the neural circuits. However, these neurological sequelae have few strong medical interventions. Designer receptors exclusively activated by designer drugs (DREADDs) are important chemogenetic tools capable of precisely modulating the activity of neural circuits. They have been suggested to have therapeutic effects on multiple neurological diseases. Despite this, no empirical research has explored the effects of DREADDs on functional recovery after ICH. We aimed to explore whether the long-term excitation of glutamatergic neurons in primary motor cortex (M1) by DREADD could promote functional recovery after ICH. We used CaMKII-driven Gq/Gi-DREADDs to activate/inhibit M1 glutamatergic neurons for 21 consecutive days, and examined their effects on behavioral and cognitive deficits caused by ICH in a mouse model of ICH targeting striatum. Long-term chemogenetic activation of the M1 glutamatergic neurons increased the spatial memory and sensorimotor ability of mice suffering from ICH. It also attenuated the mitochondrial dysfunctions of striatal neurons by raising the ATP levels and mitochondrial membrane potential while decreasing the 8-OHdG levels. These results strongly suggest that selective stimulation of the M1 glutamatergic neurons contributes to functional recovery after ICH presumably through alleviation of mitochondrial dysfunctions.

Cerebrospinal Fluid Free Fatty Acid Levels Are Associated with Stroke Subtypes and Severity in Chinese Patients with Acute Ischemic Stroke.

OBJECTIVE: To assess the clinical significance of cerebrospinal fluid (CSF) free fatty acid (FFA) levels in Chinese patients with acute ischemic stroke. METHODS: From December 2011 to October 2014, all patients with first-ever acute ischemic stroke were recruited to participate in the study. CSF levels of FFAs were assayed at 4 time points, and severity of stroke was evaluated with the National Institutes of Health Stroke Scale (NIHSS) score on admission. RESULTS: Median CSF FFA levels were significantly (P < 0.0001) higher in patients with stroke compared with control subjects. CSF FFA levels reflected the disease severity of acute ischemic stroke. There were significant positive associations between CSF FFA levels and NIHSS scores (r = 0.424, P < 0.0001) and infarct volume (r = 0.289, P < 0.0001). CSF FFA levels in patients with cardioembolic (CE) stroke were significantly higher compared with patients with non-CE stroke (0.34 mmol/L [interquartile range, 0.26-0.42] vs. 0.14 mmol/L [interquartile range, 0.08-0.23]; P < 0.0001). Based on the receiver operating characteristic curve, the optimal cutoff value of CSF FFA levels as an indicator for the diagnosis of CE stroke was projected to be 0.22 mmol/L, which yielded a sensitivity of 83.3% and a specificity of 75.3%, and the area under the curve was 0.873 (95% confidence interval, 0.810-0.935). CONCLUSIONS: CSF FFA levels at the time of admission were associated with stroke severity and lesion volumes. In addition, CE stroke can be distinguished from other stroke etiologies by measuring CSF FFA levels very early.