Abstract
Neurotrophic factors (NTFs) hold potential as disease-modifying therapies for neurodegenerative disorders like Parkinson’s disease. Glial cell line-derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF), and mesencephalic astrocyte-derived neurotrophic factor (MANF) have shown neuroprotective and restorative effects on nigral dopaminergic neurons in various animal models of Parkinson’s disease. To date, however, their effects on brain neurochemistry have not been compared using in vivo microdialysis. We measured extracellular concentration of dopamine and activity of dopamine neurochemistry-regulating enzymes in the nigrostriatal system of rat brain. NTFs were unilaterally injected into the striatum of intact Wistar rats. Brain microdialysis experiments were performed 1 and 3 weeks later in freely-moving animals. 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. Although GDNF did not affect the extracellular level of dopamine, we found significantly elevated tyrosine hydroxylase (TH) and catechol-O-methyltransferase (COMT) activity and decreased monoamine oxidase A (MAO-A) activity in striatal tissue samples 1 week after GDNF injection. The results show that GDNF, CDNF, and MANF have divergent effects on dopaminergic neurotransmission, as well as on dopamine synthetizing and metabolizing enzymes. Although the cellular mechanisms remain to be clarified, knowing the biological effects of exogenously administrated NTFs in intact brain is an important step towards developing novel neurotrophic treatments for degenerative brain diseases.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative disorder which holds an unmet need for a curative treatment
The effects of intrastriatally injected Neurotrophic factors (NTFs) on dopamine release from nigrostriatal dopaminergic neurons were examined in two consecutive microdialysis experiments, at 1 and 3 weeks after the stereotaxic surgery, in freely-moving rats
To study the ability of NTFs to alter stimulus-evoked release of dopamine in the striatum, dopaminergic nerve terminals were first depolarized by administrating high concentration of potassium via reverse dialysis which caused an extensive increase in the extracellular concentration of dopamine in all treatment groups (Fig. 2a, b)
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disorder which holds an unmet need for a curative treatment. Neurotrophic factors (NTFs) are endogenous secretory proteins which promote differentiation, maintenance, function, and plasticity of the nervous system and help neurons to recover after an injury [4,5,6,7]. Due to these trophic effects, NTFs are considered as potential disease-modifying therapies for. In in vivo lesion models, these NTFs increase the survival of midbrain dopamine cells and fibers and improve aberrant motor performance suggesting enhanced dopaminergic function. If we want to look upon NTFs as a novel therapeutic approach for PD, it is crucial to understand how exogenously administered, non-physiological concentrations of NTFs influence the normal nigrostriatal neurochemistry and neurotransmitter homeostasis
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