The effects of chronic neuroinflammation on cognition and behaviour in the GFAP-IL6 transgenic mouse and an investigation of the nootropic AGE inhibitor Tenilsetam

Abstract

Neurodegenerative and neurological disorders are incurable diseases that represent an enormous burden both financially and in terms of human suffering. Chronic neuroinflammation, demonstrated by the activation of microglia and astrocytes and the release of reactive oxygen species and pro-inflammatory cytokines, has been identified as one of the major factors in the pathogenesis of several neurological, neurodegenerative and psychiatric diseases. Understanding the underlying neuroinflammation and developing therapies that can target the inflammatory and degenerative processes is a key strategy toward finding treatments to cure these diseases. The effects of chronic neuroinflammation on cognition and behaviour were investigated in the glial fibrillary acidic protein promoter-interleukin 6 (GFAP-IL6) transgenic mouse. In this model, localised chronic neuroinflammation is mediated through the sustained, overexpression of the pro-inflammatory cytokine IL-6 (IL-6). The therapeutic potential of the nootropic compound tenilsetam was tested in this model to examine possible anti-inflammatory and cognitive enhancing effects. At the age of 3 months, heterozygous GFAP-IL6 mice (n=33) and their non-transgenic littermates (C57/BL6J) (n=35) were introduced to either a tenilsetam enriched pellet diet (70mg/kg daily dose) or control pellet diet. Following 3 months of the diet the mice were subjected to a behavioural test battery (6 months of age) that included the elevated plus maze (EPM), open field test (OF), Barnes maze (BM) and functional observational tests. The findings of this study showed that at the age of 6 months, the GFAP-IL6 mice presented with alterations in anxiety-related behaviour in the EPM and OF, exhibiting a strong anxiolytic-like phenotype. GFAP-IL6 mice also displayed an ataxic phenotype with increased abnormalities in gait and kyphosis scores and had a reduced food consumption, however did not differ in weight gain compared to WT mice. Cognitive dysfunction in the GFAP-IL6 mouse was not detected in the BM. Tenilsetam exerted clear anxiolytic-like effects in the OF, increasing the percentage of time and distance in the centre which was particularly pronounced among male mice. Tenilsetam reduced ambulation and explorative behaviour in the EPM. There were no cognition enhancing properties indicated for tenilsetam in the BM, however the anxiolytic-like effects of tenilsetam may be a confounding factor. Among WT mice tenilsetam was associated with increased food consumption and weight gain, revealing potential as an appetite stimulant. However among GFAP-IL6 mice tenilsetam exerted the opposite effect in reducing food consumption.

Date of Award	2018
Original language	English