TREATMENT WITH A CHOLINERGIC PRECURSOR IN AN ANIMAL MODEL OF CEREBROVASCULAR DISEASE: INSIGHTS INTO MECHANISMS OF NEUROPROTECTIVE ACTIVITY

Cholinergic hypofunction is a common trait of adult-onset dementia including Alzheimer’s disease (AD) and vascular dementia (VaD). Cholinergic replacing approaches represent an obvious strategy for treating cognitive dysfunctions due to impaired cholinergic neurotransmission. Cholinergic precursors increasing choline availability and acetylcholine synthesis/release were among the first approaches tried for countering cognitive impairment typical of AD or VaD. Alpha-gliceryl-phosphoryl-choline (GPC) is among cholinergic precursors the most effective in enhancing acetylcholine biosynthesis and release in animal models. Arterial hypertension is the main risk factor for stroke and plays a role in the development of VaD. An association between hypertension and reduced cerebral blood flow is documented and arterial hypertension in midlife is associated with a higher probability of cognitive impairment. Spontaneously hypertensive rats (SHR) are a rat strain investigated for assessing hypertensive brain damage and treatment of it. They are characterized by time-dependent rise of arterial blood pressure, brain atrophy, glial reaction and cholinergic hypofunction. These phenomena are shared to some extent with hypertensive brain damage and VaD. Treatment of SHR for 4 weeks treatment with 150 mg/kg/day of GPC countered the nerve cell loss in zones II, III and IV of frontal cortex and in the CA1 subfield of hippocampus and dentate gyrus . The compound reduced also parenchymal astrocytes hyperplasia and hypertrophy in the hippocampus of SHR. No significant changes in the size of perivascular astrocytes were observed in SHR, whereas the expression of the blood brain barrier (BBB) marker aquaporin-4 increased in SHR. This phenomenon was countered by GPC treatment. An increased expression of choline and of vesicular acetylcholine transporters (VAChT) was observed in different brain areas of SHR. This increase probably represents an up-regulation to counter cholinergic deficit of SHR. Treatment with GPC further increased choline transporter and to a greater extent VAChT expression. Besides to an activity on cholinergic markers, GPC increased neuronal surveillance, prevented astrogliosis, reversed BBB changes and improved micro-vessels inflammatory pattern of SHR. GPC protective effect is probably due to its interference with membrane phospholipids and/or to an enhancement of cholinergic neurotransmission mechanisms. These findings may explain data of clinical trials reporting an improvement by GPC of cognitive function in subjects suffering from cerebrovascular disorders.