Spasticity is one of the most physically debilitating disabilities following stroke and may slow down the potential success of rehabilitation. Glutamate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have been shown to play a crucial role in spasticity following cerebral ischemia/reperfusion (I/R) injury. Gua Lou Gui Zhi decoction (GLGZD) is a well-known traditional Chinese formula that has long been used clinically in China to treat muscular spasticity following stroke, epilepsy or spinal cord injury. However, the precise mechanisms behind its neuroprotective and anti-spasticity effects remain poorly understood. In the present study, using a rat model of focal cerebral I/R injury, we evaluated the neuroprotective and anti-spasticity effects of GLGZD and investigated the underlying mechanisms. We found that GLGZD improved neurological deficits and reduced infarct volumes in cerebral I/R-injured rats. In addition, GLGZD reduced cerebral ischemic spasticity since it improved the screen test and Hoffman's reflex (H-reflex) scores. It also reduced glutamate levels in the cerebrospinal fluid and altered the expression of the AMPA receptor subunits. Our data demonstrate that GLGZD exerts neuroprotective and anti-spasticity effects in a cerebral ischemia model via the modulation of glutamate levels and AMPA receptor expression.
Excessive
glutamate-mediated overactivation of metabotropic glutamate
receptor 1 (mGluR1) plays a leading role in neuronal apoptosis following
subarachnoid hemorrhage (SAH). TAT-mGluR1, a fusion peptide consisting
of a peptide spanning the calpain cleavage site of mGluR1α and
the trans-activating regulatory protein (TAT) of HIV, effectively
blocks mGluR1α truncation and protects neurons against excitotoxic
damage. This study investigated the effects of TAT-mGluR1 on neuronal
apoptosis in the rat SAH model. Here, we report that SAH caused activation
of calpain and truncation of mGluR1α; intraperitoneally administered
TAT-mGluR1 did not affect calpain activity, while it blocked truncation
of mGluR1α after SAH. Intraperitoneally administered FITC-labeled
TAT-mGluR1 was colocalized with mGluR1α in thecortex after SAH.
Furthermore, TAT-mGluR1 significantly improved the neurological deficit,
increased p-PI3K, p-Akt, and p-GSK3β, downregulated Bax, upregulated
Bcl-2, and reduced cortical apoptosis in the basal cortex at 24 h
after SAH. These findings indicated that TAT-mGluR1 acted against
SAH-induced cell apoptosis through preventing mGluR1α truncation.
Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1), as the primary oxidized low-density lipoprotein (ox-LDL) receptor on endothelial cells, plays a crucial role in endothelial injury, which is a driving force in the initiation and development of atherosclerosis. Our previous studies have shown that ethanol extract of propolis (EEP) promotes reverse cholesterol transport and inhibits atherosclerotic lesion development. However, the protective effects of EEP against ox-LDL-induced injury in endothelial cells and the underlying mechanisms are still unknown. This study was designed to test the hypothesis that EEP attenuates ox-LDL-induced endothelial oxidative injury via modulation of LOX-1-mediated oxidative stress. Our results showed that exposure of human umbilical vein endothelial cells (HUVECs) to ox-LDL (100 mg/L) led to the decrease in cell viability and increase in lactate dehydrogenase (LDH) release, caspase-3 activation, and apoptosis, whereas pretreatment with EEP (7.5, 15 and 30 mg/L) protected against such damages in a dose-dependent manner. In addition, EEP mitigated ox-LDL uptake by HUVECs and attenuated ox-LDL-upregulated LOX-1 expression both at the mRNA and protein levels. Moreover, EEP suppressed the ox-LDL-induced oxidative stress as assessed by decreased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, reactive oxygen species (ROS), and malondialdehyde (MDA) generation as well as increased antioxidant enzyme activities. Similar results were observed in the anti-LOX-1 antibody or diphenyleneiodonium (DPI)-pretreated HUVECs. These data indicate that EEP may protect HUVECs from ox-LDL-induced injury and that the mechanism at least partially involves its ability to inhibit endothelial LOX-1 upregulation and subsequent oxidative stress.
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