Dataset Information

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.

SUBMITTER: El-Mezayen NS

PROVIDER: S-EPMC10352881 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

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

El-Mezayen Nesrine Saeid NS Attia Mennat-Allah Magdy MM Shafik Mohanad Yehia MY Gowied Hadeer Galal HG Abdel-Aal Hadeer Ahmed HA Abdel-Hady Sara Medhat SM Ghazy Mostafa Said MS

CNS neuroscience & therapeutics 20230322 8

<h4>Introduction</h4>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<sub>A</sub> ) homeostasis. Activated-stellate cells lose their V<sub>A</sub> -storage capacity, and this w ...[more]

PMID: 36949616

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Project description:Astrocytes are important glia cell type in the central nervous system. These cells can undergo transformation to a reactive state upon injury such as focal ischemic stroke (FIS). Reactive astrocytes are distinct from normal or homeostatic astrocytes in morphology, protein profiles and metabolic functions. Glial cell-derived neurotrophic factor (GDNF) was discovered as a potent survival neurotrophic factor for multiple subtypes of neurons and can be released from reactive astrocytes. In our previous study, we found that GDNF expression was upregulated in reactive astrocytes following ischemic stroke. Specific knock out of GDNF in reactive astrocytes exacerbated brain damage and motor deficits after ischemic stroke. Here, using in vitro and in vivo ischemia models, we investigated the effects of GDNF overexpression in astrocytes on neuronal survival and brain recovery after ischemia. We observed that astrocyte specific GDNF overexpression by viral transduction could decrease brain infarction and promote motor function recovery after photothrombosis (PT)-induced FIS. In addition, GDNF overexpression in astrocytes could increase the proliferation of reactive astrocytes and reduce oxidative stress after PT. Using the oxygen-glucose deprivation (OGD) model of cultured astrocytes, we confirmed that this ischemic insult could upregulate GDNF expression and increase its release to extracellular space. Transfection of GDNF DNA plasmid could further increase GDNF release after OGD. To further study the effects of reactive astrocytes-derived extracellular GDNF on neuronal survival after ischemia, cultured neurons subjected to OGD were exposed to astrocyte conditioned medium (ACM). The ACM collected from OGD subjected astrocyte culture could significantly reduce neuronal death, while neutralizing antibodies against GDNF and its receptors including GFRα1, RET and p-RET could suppress this beneficial effect. We also found that reactive astrocytes-derived GDNF could trigger the activation of RET receptors in cultured neurons and suppress neuronal mitochondrial fission and caspase-dependent cell apoptosis after OGD. Overall, our results indicate that reactive astrocytes-derived GDNF could play an important role in neuronal survival and functional recovery and underscore the non-cell autonomy underlying astrocyte-neuron interactions in brain repair after ischemic stroke.

Dataset Information

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

Introduction

Methods

Results

Conclusion

Publications

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

Similar Datasets

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