Reactive astrocytes targeting with oral vitamin A: Efficient neuronal regeneration for Parkinson's disease treatment and reversal of associated liver fibrosis

Abstract

Introduction: A recent approach to cure neurodegenerative diseases is to reprogram fibroblasts into functioning neurons using multiple exogenous transcription factors (TFs) and micro-RNAs. Administering agents that can endogenously induce these TFs may bypass the limitations of this approach. Astrocytes may represent a part of the extrahepatic-stellate system involved in vitamin-A (V_A ) homeostasis. Activated-stellate cells lose their V_A -storage capacity, and this was previously applied for hepatic-stellate cells (HSCs) targeting to treat liver fibrosis. Accordingly, it is hypothesized that Parkinson's disease (PD) may be coupled with retinoid depletion that may extract V_A from V_A -rich-HSCs triggering liver fibrosis. Thus, V_A administration may selectively target V_A -deficient reactive astrocytes and HSCs. Besides, V_A has the regenerative capability and may induce endogenous-TFs generation.

Methods: Fluorescently labeled V_A -coupled liposomes (FLV) were traced using confocal laser microscope in rats with induced PD for detecting brain accumulation and uptake into fluorescently labeled astrocytes. Liver fibrosis associated with PD was assessed biochemically and histopathologically, while V_A deficiency was confirmed by assessing retinol-binding protein gene expression in the brain and liver. Multiple V_A doses were tested for reversing PD-associated liver fibrosis, generating TFs (involved in reprograming astrocytes/fibroblasts into different neuronal types) and capability of dopaminergic-neurons regeneration.

Results: Fluorescently labeled V_A -coupled liposomes revealed selective brain accumulation and uptake into astrocytes. PD was associated with significant liver fibrosis and V_A deficiency in the brain and liver. Furthermore, V_A -medium dose (VAMD) was the optimum one for reversing PD-associated liver fibrosis, generating multiple astrocytes/fibroblasts reprogramming TFs, regenerating dopaminergic neurons, and improving PD.

Conclusion: V_A -medium dose pursued brain targeting in PD with the potential capability of regenerating neurons and restoring dopaminergic transmission. This may place this therapy as an essential treatment in PD management protocol.

Keywords: Parkinson's disease; astrocytes; liver fibrosis; reprogramming; vitamin A.