Inhibition of Apoptosis in a Model of Ischemic Stroke Leads to Enhanced Cell Survival, Endogenous Neural Precursor Cell Activation and Improved Functional Outcomes.

Stroke results in neuronal cell death, which causes long-term disabilities in adults. Treatment options are limited and rely on a narrow window of opportunity. Apoptosis inhibitors demonstrate efficacy in improving neuronal cell survival in animal models of stroke. However, many inhibitors non-specifically target apoptosis pathways and high doses are needed for treatment. We explored the use of a novel caspase-3/7 inhibitor, New World Laboratories (NWL) 283, with a lower IC50 than current caspase-3/7 inhibitors. We performed in vitro and in vivo assays to determine the efficacy of NWL283 in modulating cell death in a preclinical model of stroke. In vitro and in vivo assays show that NWL283 enhances cell survival of neural precursor cells. Delivery of NWL283 following stroke enhances endogenous NPC migration and leads to increased neurogenesis in the stroke-injured cortex. Furthermore, acute NWL283 administration is neuroprotective at the stroke injury site, decreasing neuronal cell death and reducing microglia activation. Coincident with NWL283 delivery for 8 days, stroke-injured mice exhibited improved functional outcomes that persisted following cessation of the drug. Therefore, we propose that NWL283 is a promising therapeutic warranting further investigation to enhance stroke recovery.

Cholinergic upregulation by optogenetic stimulation of nucleus basalis after photothrombotic stroke in forelimb somatosensory cortex improves endpoint and motor but not sensory control of skilled reaching in mice.

A network of cholinergic neurons in the basal forebrain innerve the forebrain and are proposed to contribute to a variety of functions including cortical plasticity, attention, and sensorimotor behavior. This study examined the contribution of the nucleus basalis cholinergic projection to the sensorimotor cortex on recovery on a skilled reach-to-eat task following photothrombotic stroke in the forelimb region of the somatosensory cortex. Mice were trained to perform a single pellet skilled reaching task and their pre and poststroke performance, from Day 4 to Day 28 poststroke, was assessed frame-by-frame by video analysis with endpoint, movement and sensorimotor integration measures. Somatosensory forelimb lesions produced impairments in endpoint and movement component measures of reaching and increased the incidence of fictive eating, a sensory impairment in mistaking a missed reach for a successful reach. Upregulated acetylcholine (ACh) release, as measured by local field potential recording, elicited via optogenetic stimulation of the nucleus basalis improved recovery of reaching and improved movement scores but did not affect sensorimotor integration impairment poststroke. The results show that the mouse cortical forelimb somatosensory region contributes to forelimb motor behavior and suggest that ACh upregulation could serve as an adjunct to behavioral therapy for acute treatment of stroke.

Aqueous raw and ripe Pu-erh tea extracts alleviate obesity and alter cecal microbiota composition and function in diet-induced obese rats.

Pu-erh tea is attracting increased attention worldwide because of its unique flavor and health effects, but its impact on the composition and function of the gut microbiota remains unclear. The aim of this study was to investigate the effects of aqueous extracts of fermented (ripe) and non-fermented (raw) Pu-erh teas on the composition and function of the intestinal microbiota of rats with diet-induced obesity. We conducted a comparative metagenomic and meta-proteomic investigation of the microbial communities in cecal samples taken from obese rats treated with or without extracts of raw or ripe Pu-erh teas. By analyzing the composition and diversity of 16S rRNA amplicons and expression profiles of 814 distinct proteins, we found that despite differences in the chemical compositions of raw and ripe Pu-erh teas, administration of either tea at two doses (0.15- and 0.40-g/kg body weight) significantly (P < 0.05) increased microbial diversity and changed the composition of cecal microbiota by increasing the relative abundances of Firmicutes and decreasing those of Bacteroidetes. Community metabolic processes, including sucrose metabolism, glycolysis, and syntheses of proteins, rRNAs, and antibiotics were significantly (P < 0.05) promoted or had a tendency (0.10 < P < 0.05) to be promoted due to the enrichment of relevant enzymes. Furthermore, evidence at population, molecular, and metabolic levels indicated that polyphenols of raw Pu-erh tea and their metabolites potentially promote Akkermansia muciniphila growth by stimulating a type II and III secretion system protein, the elongation factor Tu, and a glyceraldehyde-3-phosphate dehydrogenase. This study provides new evidence for the prebiotic effects of Pu-erh tea.