Abstract
Impaired cerebral hemodynamic autoregulation, vasoconstriction, and cardiovascular and metabolic dysfunctions cause cerebral hypoperfusion (CH) that triggers pro-oxidative and inflammatory events. The sequences linked to ion-channelopathies and calcium and glutamatergic excitotoxicity mechanisms resulting in widespread brain damage and neurobehavioral deficits, including memory, neurological, and sensorimotor functions. The vasodilatory, anti-inflammatory, and antioxidant activities of cucurbitacin E (CuE) can alleviate CH-induced neurobehavioral impairments. In the present study, the neuroprotective effects of CuE were explored in a rat model of CH. Wistar rats were subjected to permanent bilateral common carotid artery occlusion to induce CH on day 1 and administered CuE (0.25, 0.5 mg/kg) and/or Bay-K8644 (calcium agonist, 0.5 mg/kg) for 28 days. CH caused impairment of neurological, sensorimotor, and memory functions that were ameliorated by CuE. CuE attenuated CH-triggered lipid peroxidation, 8-hydroxy-2′-deoxyguanosine, protein carbonyls, tumor necrosis factor-α, nuclear factor-kappaB, myeloperoxidase activity, inducible nitric oxide synthase, and matrix metalloproteinase-9 levels in brain resulting in a decrease in cell death biomarkers (lactate dehydrogenase and caspase-3). CuE decreased acetylcholinesterase activity, glutamate, and increased γ-aminobutyric acid levels in the brain. An increase in brain antioxidants was observed in CuE-treated rats subjected to CH. CuE has the potential to alleviate pathogenesis of CH and protect neurological, sensorimotor, and memory functions against CH.
Highlights
Cerebral hypoperfusion (CH) originates from cardiovascular abnormalities that result in severe neurobehavioral deficits similar to Alzheimer’s-type dementia and vascular cognitive impairment and dementia (Dong et al, 2018)
Administration of BayK8644 (Ca2+ agonist) significantly attenuated cucurbitacin E (CuE) (0.5 mg/kg) induced decline in mNSS in rats exposed to cerebral hypoperfusion (CH) relative to rats that were subjected to CuE (0.5 mg/kg) and CH surgery
CuE (0.25 and 0.5 mg/kg) post-treatment in rats subjected to CH attenuated the memory deficits (p < .01, p < .001) relative to rats that were exposed to CH and vehicle administrations (Figure 2A)
Summary
Cerebral hypoperfusion (CH) originates from cardiovascular abnormalities that result in severe neurobehavioral deficits similar to Alzheimer’s-type dementia and vascular cognitive impairment and dementia (Dong et al, 2018). A pathogenic increase in free radicals depletes endogenous antioxidants, and instigates catastrophic events of oxidative stress and inflammation in the hypoperfused brain (Chen et al, 2011) Ion channelopathy, such as hyperactivation of postsynaptic N-methyl D-aspartate receptors (NMDAR), leads to a calcium (Ca2+) influx that initiates proteolytic mechanisms (e.g., calpains) and Ca2+-dependent cell death pathways (e.g., caspase-3). Free radicals, inflammatory molecules, proteolytic enzymes (e.g., matrix metalloproteinases, myeloperoxidase), and adhesion molecules damage the vascular architecture in the brain, including the blood–brain barrier (BBB) (Wang et al, 2020) These events lead to infiltration of neutrophils and monocytes and activation of macrophages and microglia that further amplify brain damage (Liu and Zhang, 2012). Inhibition of glutamatergic excitatory drive and reestablishment of CBF can alleviate the oxidative and inflammatory insult and protect neurobehavioral functions (Farkas et al, 2002)
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