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Great new Study. Will have to review a few more times. Some initial highlights:
One week after the treatment, we observed enhanced stimulus-evoked release of dopamine in the striatum of MANF-treated rats, but not in rats treated with GDNF or CDNF. MANF also increased dopamine turnover.
Our results may indicate that MANF can enhance the dynamics of calcium mediated membrane fusion of presynaptic dopamine vesicles or increase the proportion of readily releasable vesicles as demonstrated by elevated potassium-evoked release of dopamine.
To this day, the cornerstone of the treatment of PD has been pharmacological substitution of striatal dopamine with initially good efficacy, but no effect on disease progression. NTFs are regarded as the first potential disease modifying therapy for PD as they are able to halt the progression of neurodegeneration and restore aberrant neuronal function in various experimental settings. However, clinical trials with NTFs show conflicting results. Therefore, it is important to better understand the effects of NTFs on dopaminergic functions of non-lesioned brain. Our current results reveal divergent biological effects of exogenously administrated GDNF, CDNF, and MANF. MANF is able to potentiate stimulus-evoked dopaminergic neurotransmission and enhance dopamine turnover in the brain of freely-moving rats. GDNF, on the other hand, increases the activity of TH and COMT and decreases the activity of MAO-A. This study gives an insight into the long-lasting changes in dopamine synthesis, release and metabolism after a single intrastriatal NTF injection which is highly relevant information for the development of novel therapeutic strategies for neurodegenerative diseases. However, further studies are needed to clarify the cellular mechanisms by which the NTFs produce their effects on neuronal homeostasis seen in this study.
One week after the treatment, we observed enhanced stimulus-evoked release of dopamine in the striatum of MANF-treated rats, but not in rats treated with GDNF or CDNF. MANF also increased dopamine turnover.
Our results may indicate that MANF can enhance the dynamics of calcium mediated membrane fusion of presynaptic dopamine vesicles or increase the proportion of readily releasable vesicles as demonstrated by elevated potassium-evoked release of dopamine.
To this day, the cornerstone of the treatment of PD has been pharmacological substitution of striatal dopamine with initially good efficacy, but no effect on disease progression. NTFs are regarded as the first potential disease modifying therapy for PD as they are able to halt the progression of neurodegeneration and restore aberrant neuronal function in various experimental settings. However, clinical trials with NTFs show conflicting results. Therefore, it is important to better understand the effects of NTFs on dopaminergic functions of non-lesioned brain. Our current results reveal divergent biological effects of exogenously administrated GDNF, CDNF, and MANF. MANF is able to potentiate stimulus-evoked dopaminergic neurotransmission and enhance dopamine turnover in the brain of freely-moving rats. GDNF, on the other hand, increases the activity of TH and COMT and decreases the activity of MAO-A. This study gives an insight into the long-lasting changes in dopamine synthesis, release and metabolism after a single intrastriatal NTF injection which is highly relevant information for the development of novel therapeutic strategies for neurodegenerative diseases. However, further studies are needed to clarify the cellular mechanisms by which the NTFs produce their effects on neuronal homeostasis seen in this study.
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