Cerebrovascular Disease Related to Hypertension: Effects of Antioxidant and Cholinergic Precursor Molecules

Background. A major risk factor for cerebral vascular disease and cognitive impairment is hypertension. Increased arterial wall thickness and elevated blood pressure cause hypertension. Moreover, many studies have shown that cerebrovascular alterations may cause disease in hypertensive individuals' brains because of an increase in reactive oxygen species, neuroinflammation, and cholinergic dysfunction. The effects of hypertension on the brain lead to cognitive decline and dementia. Increasing reactive oxygen species and impairment of cholinergic pathways are the mechanisms of hypertension-induced cerebrovascular alterations. In spontaneously hypertensive rats as a model of essential hypertension and brain injury, neural alterations, blood-brain barrier dysfunction, and gliosis were observed. Aim. The study aimed to determine whether choline alphoscerate (GPC) and (+) thioctic acid [(+) TIO], either alone or in combination, were investigated for their potential neuroprotective properties. GPC is a choline-containing phospholipid known for its ability to enhance cholinergic neurotransmission. The (+) TIO eutomer has been shown to exhibit greater antioxidant and anti- inflammatory activity than its racemic counterpart. Methods. Hypertensive rats aged 24 weeks were treated with GPC and (+) TIO individually or in combination. Normotensive age matched Wistar Kyoto rats were used as control. To study the oxidative status, 4-hydroxynonenal (4-HNE) concentration, protein oxidation was measured in the brain sample. For the assessment of the inflammatory process, the frontal cortex and the hippocampus were collected for western blot and immunohistochemistry investigations of glial, BBB and neuroinflammatory and the cholinergic markers. Results. In hypertensive rats, the blood pressure was higher than in normotensive ones. After four weeks of treatment with GPC and (+) TIO, slight reductions in systolic blood pressure were observed. OxyBlot in the brain showed an increase of oxidative state proteins in SHR. Based on Western blot and immunohistochemistry studies, GPC alone was able to restore the protein levels in neuronal nuclei. There was no difference between the two compounds regarding the downregulation of synaptic proteins in hypertensive rats. However, GPC and (+) TIO alone or in combination reduced astrogliosis, microglial activation, and decreased levels of the proinflammatory cytokine tumor necrosis factor alpha. It was observed that treatments partially restored the modulation of the blood-brain barrier markers aquaporin-4 and glucose transporter-1 in hypertensive rats. Because of the cholinergic neurotransmission mechanism of GPC, it was able to increase the expression level of vesicular acetylcholine transporter in brain areas of SHR. The increase expression of nAChRα7 with the GPC and the GPC and (+) TIO may suggest a protective effect mediated by the cholinergic anti-inflammatory pathway. Conclusion. Our findings can contribute to better defining the role of the inflammatory processes of neurovascular unit in brain disorders characterized by vascular impairment. Based on the evidence, treatment with GPC alone and GPC plus (+)TIO attenuates the glial reaction and the neuroinflammation in the two brain areas, providing neuroprotection by the stimulation of the cholinergic pathways. Furthermore, that may be a therapeutic strategy worth exploring in further preclinical and clinical research.