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.