Exendin-4 and linagliptin attenuate neuroinflammation in a mouse model of Parkinson's disease.

Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson's disease in patients with diabetes mellitus. Therefore, using these two treatments may help treat Parkinson's disease. To further investigate the mechanisms of action of these two compounds, we established a model of Parkinson's disease by treating mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and then subcutaneously injected them with the glucagon-like peptide-1 receptor agonist exendin-4 or the dipeptidyl peptidase 4 inhibitor linagliptin. We found that both exendin-4 and linagliptin reversed motor dysfunction, glial activation, and dopaminergic neuronal death in this model. In addition, both exendin-4 and linagliptin induced microglial polarization to the anti-inflammatory M2 phenotype and reduced pro-inflammatory cytokine secretion. Moreover, in vitro experiments showed that treatment with exendin-4 and linagliptin inhibited activation of the nucleotide-binding oligomerization domain- and leucine-rich-repeat- and pyrin-domain-containing 3/caspase-1/interleukin-1ß pathway and subsequent pyroptosis by decreasing the production of reactive oxygen species. These findings suggest that exendin-4 and linagliptin exert neuroprotective effects by attenuating neuroinflammation through regulation of microglial polarization and the nucleotide-binding oligomerization domain- and leucine-rich-repeat- and pyrin-domain-containing 3/caspase-1/interleukin-1ß pathway in a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Therefore, these two drugs may serve as novel anti-inflammatory treatments for Parkinson's disease.

Exosomes derived from bone marrow mesenchymal stem cells protect the injured spinal cord by inhibiting pericyte pyroptosis.

Mesenchymal stem cell (MSC) transplantation is a promising treatment strategy for spinal cord injury, but immunological rejection and possible tumor formation limit its application. The therapeutic effects of MSCs mainly depend on their release of soluble paracrine factors. Exosomes are essential for the secretion of these paracrine effectors. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-EXOs) can be substituted for BMSCs in cell transplantation. However, the underlying mechanisms remain unclear. In this study, a rat model of T10 spinal cord injury was established using the impact method. Then, 30 minutes and 1 day after spinal cord injury, the rats were administered 200 µL exosomes via the tail vein (200 µg/mL; approximately 1 × 106 BMSCs). Treatment with BMSC-EXOs greatly reduced neuronal cell death, improved myelin arrangement and reduced myelin loss, increased pericyte/endothelial cell coverage on the vascular wall, decreased blood-spinal cord barrier leakage, reduced caspase 1 expression, inhibited interleukin-1ß release, and accelerated locomotor functional recovery in rats with spinal cord injury. In the cell culture experiment, pericytes were treated with interferon-γ and tumor necrosis factor-α. Then, Lipofectamine 3000 was used to deliver lipopolysaccharide into the cells, and the cells were co-incubated with adenosine triphosphate to simulate injury in vitro. Pre-treatment with BMSC-EXOs for 8 hours greatly reduced pericyte pyroptosis and increased pericyte survival rate. These findings suggest that BMSC-EXOs may protect pericytes by inhibiting pyroptosis and by improving blood-spinal cord barrier integrity, thereby promoting the survival of neurons and the extension of nerve fibers, and ultimately improving motor function in rats with spinal cord injury. All protocols were conducted with the approval of the Animal Ethics Committee of Zhengzhou University on March 16, 2019.

Ischemic Postconditioning Alleviates Brain Edema After Focal Cerebral Ischemia Reperfusion in Rats Through Down-Regulation of Aquaporin-4.

Cerebral edema is a serious complication associated with cerebral ischemia/reperfusion (I/R). Aquaporin-4 (AQP4) plays a role in generating postischemic edema after reperfusion. Recently, ischemic postconditioning (Postcond) has been shown to produce neuroprotective effects and reduce brain edema in rats after cerebral I/R. It is unclear if ischemic Postcond alleviates brain edema injury through regulation of AQP4. In this study, middle cerebral artery occlusion (MCAO) was induced in rats by filament insertion for 2 h following 24-h reperfusion: ischemic Postcond treatment was performed before reperfusion in the experimental group. We used the wet-dry weight ratio and transmission electron microscopy to evaluate brain edema after 24 h of reperfusion. We used immunohistochemistry and Western blot analyses to evaluate the distribution and expression of AQP4. Ischemic Postcond significantly reduced the water content of the brain tissue and swelling of the astrocytic foot processes. AQP4 expression increased in the I/R and Postcond groups compared to the sham group, but it decreased in the Postcond group compared to the I/R group. The results of our study suggest that ischemic Postcond effectively reduces brain edema after reperfusion by inhibiting AQP4 expression. The data in this study support the use of ischemic Postcond for alleviating brain edema after cerebral I/R.

Ischemic postconditioning protects the neurovascular unit after focal cerebral ischemia/reperfusion injury.

Recently, cerebral ischemic postconditioning (Postcond) has been shown to reduce infarction volume in cerebral ischemia/reperfusion (I/R) injury. However, it is unclear if ischemic Postcond offers more extensive neuroprotection than current therapies. The aim of this study was to investigate the neuroprotective effects of ischemic Postcond on the neurovascular unit (NVU). A middle cerebral artery occlusion rat model was used; cerebral infarct volumes, neurologic scores, and transmission electron microscopy were evaluated 24 h after reperfusion. We used Evans blue extravasation, immunohistochemistry, and Western blot analyses to evaluate the integrity of the blood brain barrier (BBB) and the distribution and expression of the tight junction (TJ)-associated proteins of claudin-5 and occludin in brain microvessel endothelium. The Postcond group showed significantly reduced infarct volumes and decreased neurologic impairment scores compared to the I/R group. Also, injuries to the cerebral microvascular endothelial cells, astrocytes, and neurons were minimized in the Postcond group. The permeability of the BBB increased in both the I/R and Postcond groups, but the Postcond group showed a significant decrease in permeability than the I/R group. Expression of both claudin-5 and occludin were higher in the Postcond groups compared to the I/R group, but expression of both proteins decreased in the I/R and Postcond groups compared to the sham group. The results of our study suggest that ischemic Postcond is an effective way to reduce injury to neurons, astrocytes, and endothelial cells, to increase protein expressions of TJ-associated proteins, and to improve BBB intergrity affected by focal I/R. Ischemic Postcond could protect the NVU from I/R injury.