Original Article

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

Xin JIN, Ru-huan WANG, Hui WANG, Chao-liang LONG, Hai WANG
DOI: 10.1038/aps.2015.104


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.
Keywords: ischemic stroke; pMCAO rats; choline; methyllycaconitine; neovascularization; α7 nicotinic acetylcholine receptor; HIF-1α; VEGF; angiogenesis; brain microvascular endothelial cells

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