Treatment of Stroke with a Synthetic Liver X Receptor Agonist, TO901317, Promotes Synaptic Plasticity and Axonal Regeneration in Mice

Abstract

In this study, we tested the hypothesis that TO901317 promotes synapse plasticity and axonal regeneration after stroke. Adult male C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAo) and treated with or without TO901317 starting 24 h after MCAo daily for 14 days. Axonal damage and regeneration were evaluated by immunostaining. TO901317 significantly increased synaptophysin expression and axonal regeneration, as well as decreased the expressions of amyloid betaA4 precursor protein and Nogo receptor (NgR) in the ischemic brain. To test whether TO901317 regulates the phosphorylation of phosphatidylinositol 3-kinase (p-PI3K) and Akt (p-Akt) activity in the ischemic brain, MCAo mice were treated with or without TO901317 starting 24 h after MCAo daily for 4 days and were then killed at 5 days after MCAo. TO901317 treatment significantly increased p-PI3K and p-Akt activity, but did not increase total PI3K expression in the ischemic brain. Using primary cortical neuron (PCN) culture, TO901317 significantly increased synaptophysin expression, p-PI3K activity, and decreased NgR expression compared with nontreated controls. TO901317 also significantly increased neurite outgrowth, and inhibition of the PI3K/Akt pathway by LY294002 decreased neurite outgrowth in both controls and TO901317-treated groups in cultured hypoxic PCN. These data indicate that TO901317 promotes synaptic plasticity and axonal regeneration, and that PI3K/Akt signaling activity contributes to neurite outgrowth.

Liver X receptors alpha and beta promote myelination and remyelination in the cerebellum

“…LXR activation promotes synaptic plasticity and axonal regeneration in stroke patients (11) and is required for dopaminergic neuron differentiation, which is useful for Parkinson's disease treatment (4,20). In Alzheimer's disease, LXR activation increases the number of cholinergic neurons and attenuates cognitive impairment by blocking the inflammatory process (12).…”

“…Given that the modulation of the LXR pathway is already beneficial for the treatment of other pathologies of the nervous system (11,12), our observations open new perspectives for the development of therapies targeting LXRs in demyelinating diseases.…”

Differential regulation of ABCA1 and ABCG1 gene expressions in the remodeling mouse hippocampus after entorhinal cortex lesion and liver-X receptor agonist treatment

“…The results presented here on increased hippocampal AChE and synaptophysin protein levels in the pre-lesion TO901317-treated mice are certainly consistent with these observations. They are also supported by the work of Chen et al (2010) showing that TO901317 administration stimulates synaptic remodeling and axonal regeneration in an experimental model of stroke in the mouse.…”

“…Following acclimatization, a subgroup of mice were randomly assigned to receive daily intra-peritoneal injections of 30 mg/kg/day of TO901317 in 0.125% (wt/vol) carboxymethycellulose (CMC) at one of two different starting time points and continued until sacrifice in order to assess the therapeutic potential of the treatment as prevention (7 days before lesion (ECL); n = 5) or rescue (7 days after lesion (ECL); n = 5). The choice of the 30 mg/kg/day dose was guided by previous studies which reported beneficial outcomes of TO901317 in the CNS (Chen et al, 2010;Morales et al, 2008;Riddell et al, 2007). Furthermore, a prior pilot study was conducted in our laboratory using a small set of animals.…”

Effect of a Synthetic Liver X Receptor Agonist TO901317 on Cholesterol Concentration in Goose Primary Hepatocytes

“…Another possibility is that PI3K gene transcription is coordinately regulated by LXR, because the results showed that TO901317 treatment also increased PI3K enzyme activity. Similarly, previous research has shown that in vitro primary cortical neuron culture TO901317 treatment significantly increased the p-PI3K and p-AKT activity (Chen et al, 2009). Otherwise, we observed when TO901317 concentration reached 10 μmol/L, the expression of PI3K/AKT/mTOR remained a significant high level, but the SREBP-2 mRNA level and the intracellular cholesterol concentration decreased.…”