Transient global cerebral ischemia causes loss of pyramidal cells in CA1 region of hippocampus. In this study, we investigated the neurotrophic effect of the immunosuppressant agent FK506 in rat after global cerebral ischemia. Both common carotid arteries were occluded for 20 minutes followed by reperfusion. In experimental group 1, FK506 (6 mg/kg) was given as a single dose exactly at the time of reperfusion. In the second group, FK506 was administered at the beginning of reperfusion, followed by its administration intraperitoneally (IP) 6, 24, 48, and 72 hours after reperfusion. FK506 failed to show neurotrophic effects on CA1 region when applied as a single dose of 6 mg/kg. The cell number and size of the CA1 pyramidal cells were increased, also the number of cell death decreased in this region when FK506 was administrated 48 h after reperfusion. This work supports the possible use of FK506 in treatment of ischemic brain damage.
Stroke imposes a long-term neurological disability with limited effective treatments available for neuronal recovery. Transplantation of neural stem cells (NSCs) is reported to improve functional outcomes in the animal models of brain ischemia. However, the use of cell therapy is accompanied by adverse effects, so research is growing to use cell-free extracts such as extracellular vesicles (EVs) for targeting brain diseases. In the current study, male Wistar albino rats (20 months old) were subjected to middle cerebral artery occlusion (MCAO). Then, EVs (30 μg) were injected at 2 hours after stroke onset via an intracerebroventricular (ICV) route. Measurements were done at day 7 post-MCAO. EVs administration reduced lesion volume and steadily improved spontaneous locomotor activity.EVs administration also reduced microgliosis (ionized calcium-binding adaptor molecule 1 (Iba1) + cells) and apoptotic (terminal-deoxynucleotidyl transferase mediated nick end labelling [TUNEL]) positive cells and increased neuronal survival (neuronal nuclear (NeuN) + cells) in the ischemic boundary zone (IBZ). However, it had no effect on neurogenesis within the sub-ventricular zone (SVZ) but decreased cellular migration toward the IBZ (doublecortin (DCX) + cells). The results of this study showed neuroprotective and restorative mechanisms of NSC-EVs administration, which may offer new avenues for therapeutic intervention of brain ischemia. Significance of the study: Based on our results, EVs administration can effectively reduce microglial density and neuronal apoptosis, thereby steadily improves functional recovery after MCAO. These findings provide the beneficial effect of NSC-EVs as a new biological treatment for stroke. K E Y W O R D S extracellular vesicle (EV), ischemic boundary zone (IBZ), middle cerebral artery occlusion (MCAO), neural stem cell (NSC), neurogenesis
The prefrontal cortex is the largest lobe of the brain and is consequently involved in stroke. There is no comprehensive practical pharmacological strategy for ameliorating prefrontal cortex injury induced by cerebral ischemia. Therefore, we studied the neuroprotective properties of verapamil (Ver) on mitochondrial dysfunction and morphological features of apoptosis in transient global ischemia/reperfusion (I/R). Ninety-six Wistar rats were allocated into four groups: control, I/R, I/R+Ver (10 mg/kg twice 1 hour prior to ischemia and 1 hour after reperfusion phase), and I/R+NaCl (vehicle). Animals were sacrificed, and mitochondrial dysfunction parameters (i.e., mitochondrial swelling, mitochondrial membrane potential, ATP concentration, ROS production, and cytochrome c release), antioxidant defense (i.e., superoxide dismutase, malondialdehyde, glutathione peroxidase, catalase, and caspase-3 activation), and morphological features of apoptosis were determined. The results showed that mitochondrial damage, impairment of antioxidant defense system, and apoptosis were significantly more prevalent in the I/R group in comparison with the other groups. Ver decreased mitochondrial damage by reducing oxidative stress, augmented the activity of antioxidant enzymes in the brain, and decreased apoptosis in the I/R neurons. The current study confirmed the role of oxidative stress and mitochondrial dysfunction in I/R progression and indicated the possible antioxidative mechanism of the neuroprotective activities of Ver.
Background: Ischemic stroke, as a health problem caused by the reduced blood supply to the brain, can lead to the neuronal death. The number of reliable therapies for stroke is limited. MSCs exhibit therapeutic achievement. A major limitation of MSC application in cell therapy is the short survival span. MSCs affect target tissues through the secretion of many paracrine agents including EVs. This study aimed to investigate the effect of HUCPVCs-derived EVs on apoptosis, functional recovery, and neuroprotection. Methods: Ischemia was induced by MCAO in male Wistar rats. Animals were classified into sham, MCAO, MCAO + HUCPVC, and MCAO + EV groups. Treatments began at two hours after ischemia. Expressions of apoptotic-related proteins (BAX/BCl-2 and caspase-3 and -9), the amount of TUNEL-positive cells, neuronal density (MAP2), and dead neurons (Nissl staining) were assessed on day seven post MCAO. Results: Administration of EVs improved the sensorimotor function ( p < 0.001) and reduced the apoptotic rate of Bax/Bcl-2 ratio ( p < 0.001), as well as caspases and TUNEL-positive cells ( p < 0.001) in comparison to the MCAO group. EV treatment also reduced the number of dead neurons and increased the number of MAP2 + cells in the IBZ ( p < 0.001), as compared to the MCAO group. Conclusion: Our findings showed that HUCPVCs-derived EVs are more effective than their mother’s cells in improving neural function, possibly via the regulation of apoptosis in the ischemic rats. The strategy of cell-free extracts is, thus, helpful in removing the predicaments surrounding cell therapy in targeting brain diseases.
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