Pharmacological Manipulation of the Vasoconstrictive Effects of Amyloid- β Peptides by Donepezil and Rivastigmine

Goksel      Doganay; Bereha      Khodr; George      Georgiou; Zeinab      Khalil

Abstract

The amyloid-b (Aβ) peptide has been linked to the pathology of Alzheimers disease (AD). There is now evidence to support a vasoconstrictive effect of Aβ protein that could be detected in peripheral skin microvasculature. In this study we investigated the ability of acetylcholinesterase (AChE) inhibitors, Donepezil and Rivastigmine, to modulate the vasoconstrictor activity of Aβ25-35 and Aβ1-40. The ability of these drugs to improve endothelial mediated vascular responses to acetylcholine and bradykinin subsequent to perfusion of Aβ peptides was also investigated. The vascular responses to Aβ peptides, acetylcholine, bradykinin and sodium nitroprusside and their modulation by acetylcholinesterase inhibitors were examined in the base of a vacuum induced blister raised on the rat hind footpad using laser Doppler flowmetry. Aβ25-35 (1μM) and Aβ1-40 (0.1μM) induced a vasoconstrictor effect and significantly reduced the vasodilator response to acetylcholine (100μM) and bradykinin (1μM). Donepezil (100μM) and Rivastigmine (100μM) both reduced the vasoconstrictor effect of Aβ peptides, and significantly restored the endothelial vascular response to acetylcholine. Similarly, Donepezil significantly restored the endothelial vascular response to bradykinin. The results also showed that the actions of acetylcholinesterase inhibitors are independent of a direct action on smooth muscle cell reactivity or on endothelial cell function in the absence of Aβ. The current study provides the first evidence in vivo to suggest that acetylcholinesterase inhibitors modulate the vasoconstrictive effects of Aβ peptides at the level of skin microvasculature. We raise the notion that Donepezil and Rivastigmine mediate these vascular modulatory effects via an action on Aβ-mediated vasoconstrictor mechanisms rather than an independent action on endothelial or smooth muscle cell mediated responses.

Keywords: Alzheimer's disease, Aβ peptides, acetylcholinesterase inhibitors, endothelial-dependent vasodilators, skin microvasculature

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