Naoki Tajiri

Background: The major surgical treatment for Parkinson’s disease (PD) is deep brain stimulation (DBS), but a less invasive treatment is desired. Vagus nerve stimulation (VNS) is a relatively safe treatment without cerebral invasiveness. In this study, we developed a wireless controllable electrical stimulator to examine the efficacy of VNS on PD model rats. Methods: Adult female Sprague-Dawley rats underwent placement of a cuff-type electrode and stimulator on the vagus nerve. Following which, 6-hydroxydopamine (6-OHDA) was administered into the left striatum to prepare a PD model. VNS was started immediately after 6-OHDA administration and continued for 14 days. We evaluated the therapeutic effects of VNS with behavioral and immunohistochemical outcome assays under different stimulation intensity (0.1, 0.25, 0.5 and 1 mA). Results: VNS with 0.25–0.5 mA intensity remarkably improved behavioral impairment, preserved dopamine neurons, reduced inflammatory glial cells, and increased noradrenergic neurons. On the other hand, VNS with 0.1 mA and 1 mA intensity did not display significant therapeutic efficacy. Conclusions: VNS with 0.25–0.5 mA intensity has anti-inflammatory and neuroprotective effects on PD model rats induced by 6-OHDA administration. In addition, we were able to confirm the practicality and effectiveness of the new experimental device.

With restricted therapeutic opportunities, stroke remains a relevant, critical disease necessitating study. Due to the unique aspect of ischemic strokes, finding approaches to maintain the vigor of the cerebral vasculature, such as increased angiogenesis, may protect against stroke. Ischemic strokes are caused by disruptions in blood movement in the brain, resulting in a torrent of harmful cerebrovasculature modifications. In an investigation by Pianta et al., Sprague-Dawley rats have been separated into those that undergo exercise prior to middle cerebral artery occlusion (MCAO) and those that were not exposed to physical activity preceding MCAO. The outcomes and results of the current study gave new insights into the capacity of exercise to help prevent ischemic strokes or mitigate poststroke effects. The data collected from the study suggested that rats that went through a short bout of exercise before MCAO presented superior motor performance, more active cells in the peri-infarct region, and reduced infarct sizes. When compared to the control group, the rats that went through exercise also had heightened angiogenesis and improved neuroprotection. Thus, a brief bout of physical activity preceding a stroke may provide neuroprotection by enhancing the strength of the cerebrovasculature in the brain. This notion that even an instant of physical exercise before a stroke is induced can help dampen the effects of ischemic stroke, which could lead to future techniques in preventing the ischemic stroke so that it never happens at all.

Neuroinflammation is a common therapeutic target for traumatic brain injury (TBI) due to its contribution to delayed secondary cell death and has the potential to occur for years after the initial insult. Exosomes from adipose-derived stem cells (hASCs) containing the long noncoding RNA MALAT1 are a novel, cell-free regenerative approach to long-term recovery after traumatic brain injury (TBI) that have the potential to modulate inflammation at the genomic level. The long noncoding RNA MALAT1 has been shown to be an important component of the secretome of hASCs. We isolated exosomes from hASC containing or depleted of MALAT1. The hASC-derived exosomes were then administered intravenously to rats following a mild controlled cortical impact (CCI). We followed the rats with behavior, in vivo imaging, histology, and RNA sequencing (RNA Seq). Using in vivo imaging, we show that exosomes migrate into the spleen within 1 h following administration and enter the brain several hours later following TBI. Significant recovery of function on motor behavior as well as a reduction in cortical brain injury was observed after TBI in rats treated with exosomes. Treatment with either exosomes depleted of MALAT1 or conditioned media depleted of exosomes showed limited regenerative effects, demonstrating the importance of MALAT1 in exosome-mediated recovery. Analysis of the brain and spleen transcriptome using RNA Seq showed MALAT1-dependent modulation of inflammation-related pathways, cell cycle, cell death, and regenerative molecular pathways. Importantly, our data demonstrates that MALAT1 regulates expression of other noncoding RNAs including snoRNAs. We demonstrate that MALAT1 in hASC-derived exosomes modulates multiple therapeutic targets, including inflammation, and has tremendous therapeutic potential for treatment of TBI.