Brain protection against ischemic stroke using choline as a new molecular bypass treatment

Abstract

Aim: To determine whether administration of choline could attenuate brain injury in a rat model of ischemic stroke and the underlying mechanisms.Methods: A rat model of ischemic stroke was established through permanent middle cerebral artery occlusion (pMCAO). After the surgery, the rats were treated with choline or choline plus the specific α7 nAChR antagonist methyllycaconitine (MLA), or with the control drug nimodipine for 10 days. The neurological deficits, brain-infarct volume, pial vessel density and the number of microvessels in the cortex were assessed. Rat brain microvascular endothelial cells (rBMECs) cultured under hypoxic conditions were used in in vitro experiments. Results: Oral administration of choline (100 or 200 mg·kg -1 ·d -1 ) or nimodipine (20 mg·kg -1 ·d -1 ) significantly improved neurological deficits, and reduced infarct volume and nerve cell loss in the ischemic cerebral cortices in pMCAO rats. Furthermore, oral administration of choline, but not nimodipine, promoted the pial arteriogenesis and cerebral-cortical capillary angiogenesis in the ischemic regions. Moreover, oral administration of choline significantly augmented pMCAO-induced increases in the expression levels of α7 nAChR, HIF-1α and VEGF in the ischemic cerebral cortices as well as in the serum levels of VEGF. Choline-induced protective effects were prevented by co-treatment with MLA (1 mg·kg -1 ·d -1, ip). Treatment of rBMECs cultured under hypoxic conditions in vitro with choline (1, 10 and 100 μmol/L) dose-dependently promoted the endothelial-cell proliferation, migration and tube formation, as well as VEGF secretion, which were prevented by co-treatment with MLA (1 μmol/L) or by transfection with HIF-1α siRNA. Conclusion: Choline effectively attenuates brain ischemic injury in pMCAO rats, possibly by facilitating pial arteriogenesis and cerebralcortical capillary angiogenesis via upregulating α7 nAChR levels and inducing the expression of HIF-1α and VEGF.

1H NMR metabolomic profiling elucidated attenuation of neurometabolic alterations by lercanidipine in MCAo model in rats

“…CDP‐Cho has been shown to reduce oxidative stress by increasing phosphatidylcholine levels through attenuation of phospholipase C activity . In another study, Cho angiogenic property was evidenced by promoting collateral circulation via upregulation of α7 nicotinic acetylcholine receptor, hypoxia‐inducible factor‐1α and vascular endothelial growth factor in permanent MCAo model . In the present study, the CDP‐Cho levels were decreased in MCAo control rats which were found to be elevated in lercanidipine‐treated rats.…”

Mesencephalic Electrical Stimulation Reduces Neuroinflammation after Photothrombotic Stroke in Rats by Targeting the Cholinergic Anti-Inflammatory Pathway

“…In the brain, α7nAChRs are found in both neurons [ 27 ] and non-neuronal cells such as microglia [ 28 ], astrocytes [ 29 ], and endothelial cells [ 30 ]. When α7nAChRs are stimulated by their agonist choline in a rat stroke model of permanent middle cerebral artery occlusion (MCAO), an elevated amount of α7nAChRs was recognized as well as a reduction of infarct volume and neurological deficits [ 31 ]. In the present study, the number of α7nAChR-expressing cells in the perilesional area did not differ significantly between stimulated and unstimulated animals, indicating that MLR-HFS does not regulate the expression of α7nAChR.…”

B-Vitamin and Choline Supplementation Changes the Ischemic Brain

“…In folate-deficient individuals, more methyl groups are used from choline in methylation of homocysteine (Niculescu and Zeisel, 2002). Choline might also provide protection after ischemic stroke by facilitating angiogenesis (Jin et al, 2015).…”