POSSIBLE PROTECTIVE MECHANISM OF CHOLINE ALPHOSCERATE IN BRAIN OF SPONTANEOUSLY HYPERTENSIVE RATS AS MODEL OF CEREBROVASCULAR DISEASE

Cholinergic impairment represents a common trait of adult-onset dementia including Alzheimer’s disease (AD) and vascular dementia (VaD) [1]. Cholinergic replacing approaches represent the main strategy for treating cognitive dysfunctions. It has been hypothesized that cholinergic precursors increasing choline availability and acetylcholine synthesis/release may counter cognitive impairment occurring in adult-onset dementia disorders. Choline alphoscerate (alpha-gliceryl-phosphoryl-choline, GPC) is among cholinergic precursors the most effective in enhancing acetylcholine biosynthesis and release in animal models [2]. Arterial hypertension in midlife is associated with a higher probability of cognitive impairment. Spontaneously hypertensive rat (SHR) is the rat strain extensively investigated for assessing hypertensive brain damage and treatment of it [3,4]. They are normotensive at birth and at 6-months they have a sustained hypertension. Time-dependent rise of arterial blood pressure, the occurrence of brain atrophy and glial reaction are phenomena shared to some extent with hypertensive brain damage in humans. An impaired cholinergic neurotransmission characterizes SHR, similarly as reported in VaD. The present study has assessed if long term treatment with GPC has a cerebroprotective effect on brain injury of vascular origin. Analysis was made on spontaneously hypertensive rats (SHR) used as animal model of brain vascular injury. Male SHR aged 32 weeks and age-matched normotensive Wistar–Kyoto (WKY) rats were treated for 4 weeks with GPC (150 mg/kg/day) or vehicle. Treatment with GFC countered the nerve cell loss in zones II, III and IV of frontal cortex and in the CA1 subfield of hippocampus and dentate gyrus. An astrogliosis consisting in GFAP-immunoreactive parenchymal astrocytes hyperplasia and hypertrophy was also observed primarily in the hippocampus of SHR. No significant changes in the size of perivascular astrocytes were observed in SHR compared to WKY, whereas the expression of the BBB marker aquaporin-4 decreased in SHR. This phenomenon was countered by GPC treatment. Endothelial markers and vascular adhesion molecules expression were not homogeneously affected by hypertension in both pial and intracerebral vessels. On the other hand, using immunochemical and ELISA analysis, an increased expression of choline transporters and vesicular acetylcholine transporter (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 transporters and to a greater extent VAChT. Besides its effects on cholinergic markers, GPC increases neuronal surveillance, prevents astrogliosis, reverses BBB changes and improves micro-vessels inflammatory pattern of SHR. These preclinical data suggest a re-evaluation of GPC activity in controlled clinical studies in cerebrovascular patients with cognitive dysfunction. References 1. Amenta F, Tayebati SK. Pathways of acetylcholine synthesis, transport and release as targets for treatment of adult-onset cognitive dysfunction. Curr Med Chem. 2008;15(5):488-98. 2. Tayebati SK, Amenta F. Choline-containing phospholipids: relevance to brain functional pathways. Clin Chem Lab Med. 2013 Mar 1;51(3):513-21. 3. Tayebati SK, Tomassoni D, Amenta F. Spontaneously hypertensive rat as a model of vascular brain disorder: microanatomy, neurochemistry and behavior. J Neurol Sci. 2012, 322:241-9. 4. Tomassoni D, Catalani A, Cinque C, Di Tullio MA, Tayebati SK, Cadoni A, Nwankwo IE, Traini E, Amenta F. Effects of cholinergic enhancing drugs on cholinergic transporters in the brain and peripheral blood lymphocytes of spontaneously hypertensive rats. Curr Alzheimer Res. 2012 Jan;9(1):120-7.