Modulation of Anxiety Behavior by Intranasally Administered Vaccinia Virus Complement Control Protein and Curcumin in a Mouse Model of Alzheimers Disease

A.      P. Kulkarni; D.      A. Govender; G.      J. Kotwal; L.      A. Kellaway

doi:10.2174/156720511794604598

Abstract

Widespread neuroinflammation in the central nervous system (CNS) of Alzheimers disease (AD) patients, involving pro-inflammatory mediators such as complement components, might be responsible for AD associated behavioral symptoms such as anxiety. Vaccinia virus complement control protein (VCP) and curcumin (Cur) are the bioactive compounds of natural origin shown to inhibit the in-vitro complement activation. In order to develop complement regulatory compounds which could be delivered to the CNS by a non-invasive route, VCP, its truncated version (tVCP), and Cur were administered to Wistar rats intranasally. The distribution of these compounds in cerebrospinal fluid (CSF) was studied using an enzyme linked immunosorbent assay (ELISA), using VCP and tVCP as antigens and a modified fluorimetric method (Cur). VCP and tVCP were also detected in the olfactory lobes of the rat brain using immunohistochemical analysis. These compounds were then compared for their ability to attenuate the anxiety levels in APPswePS1δE9 mice using an elevated plus maze (EPM) apparatus. VCP treatment significantly improved the exploratory behavior and reduced the anxiety behavior in APPswePS1δE9 mice. tVCP however showed an opposite effect to VCP, whereas Cur showed no effect on the anxiety behavior of these mice. When these mice were subsequently tested for their cognitive performance in the Morris water maze (MWM), they showed tendencies to collide with the periphery of the walls of MWM. This unusual activity was termed “kissperi” behavior. This newly defined index of anxiety was comparable to the anxiety profile of the VCP and tVCP treated groups on EPM. VCP can thus be delivered to the CNS effectively via intranasal route of administration to attenuate anxiety associated with AD.

Keywords: Complement, VCP, curcumin, anxiety, Alzheimer's disease (AD), neuroinflammation, elevated plus maze (EPM), Morris water maze (MWM), intranasal administration, Vaccinia virus complement control protein, tVCP, Complement regulation, C3b, QCM-D, MWM, elevated plus maze, EPM, complement regulatory proteins, CSF, CNS delivery