Enhanced glial cell line-derived neurotrophic factor mRNA expression upon (?)-deprenyl and melatonin treatments

Abstract

Glial cell line-derived neurotrophic factor (GDNF) has been shown to be a preferentially selective neurotrophic factor for dopamine (DA) neurons. In the present study, we have examined the distribution of GDNF mRNA expression in several major DA-containing cell body and terminal areas and the regulation of GDNF mRNA expression upon various pharmacological treatments. Results indicated that there is a relatively higher GDNF mRNA level in neurons of the nigrostriatal and mesolimbic dopaminergic pathways. Upon chronic 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) treatment (30 mg/ kg, i.p., for 7 days), DA level was decreased, whereas GDNF mRNA expression was increased in the striatum, suggesting that more GDNF is synthesized and expressed to cope with the neurotoxin insult. Furthermore, among several DA neuron protective and/or therapeutic agents examined, both intrastriatal injections of (-)-deprenyl (1.25 microg and 2.5 microg) and melatonin (30 microg, 60 microg, and 120 microg) significantly enhanced GDNF mRNA expression in the striatum, whereas the same concentrations of (-)-deprenyl did not affect monoamine oxidase B (MAOB) activity, although it increased glutathione peroxidase (GPx) and/or superoxide dismutase (SOD) activities. Similarly, the same concentrations of melatonin did not alter SOD or GPx activities, except that the highest dose of melatonin (120 microg) increased lipid peroxidation in the striatum. Conversely, GM1 ganglioside injection (45 microg) lacked of an effect on GDNF mRNA expression. Together, these results suggest that both (-)-deprenyl and melatonin up-regulate GDNF gene expression at threshold doses lower than that needed for altering MAOB activity and/or the antioxidant enzyme systems, respectively. These results provide new information on the neuroprotective and therapeutic mechanisms of (-)-deprenyl and melatonin on DA neurons.

Driving GDNF expression: The green and the red traffic lights

“…VPA has been shown to activate the MAPK-ERK pathway in human neuroblastoma SH-SY5Y cells (Yuan et al, 2001) suggesting that this mechanism could be responsible for the VPA-induced GDNF up-regulation observed in other studies (Castro et al, 2005;Chen et al, 2006b). Melatonin, also known to increase the expression of GDNF (Tang et al, 1998;Armstrong and Niles, 2002;Chen et al, 2003;Lee et al, 2006), is able, via the MT1 receptor, to activate the MAPK-ERK pathway (Witt-Enderby et al, 2000).…”

“…Low physiological concentrations of melatonin also caused a significant induction of GDNF mRNA expression in a neural stem cell line (Niles et al, 2004). Intrastriatal injections of melatonin significantly enhance GDNF mRNA expression in the striatum at threshold doses lower than those needed to alter the antioxidant enzyme systems (Tang et al, 1998) and GDNF levels are also elevated in the locus coeruleus of melatonin-treated rats . Melatonin also induces astroglial GDNF expression in the mouse hippocampus .…”

“…1), although some contradictory findings exist. In the striatum, an increase in GDNF mRNA or protein levels has been observed after 6-OHDA-induced (Zhou et al, 2000;Nakajima et al, 2001;FletcherTurner, 2001, 2002;Hida et al, 2003) or MPTP-induced injury (Tang et al, 1998). However, other authors have failed to detect changes in striatal GDNF levels after 6-OHDA lesion (Stromberg et al, 1993;Anastasia et al, 2007) or MPTP treatment (Inoue et al, 1999;Collier et al, 2005).…”

“…In addition, desmethylselegiline, a selegiline metabolite, also elevates GDNF mRNA and protein levels . Intrastriatal injections of selegiline significantly enhance GDNF mRNA expression in rats, whereas the same concentrations of selegiline do not affect MAO-B activity (Tang et al, 1998). Therefore, the effect of selegiline on GDNF expression seems to be independent of its effect on MAO activity but is not clear whether it involves the enhancement of the impulse mediated release of catecholamines, the so called ''catecholaminergic activity enhancement'' (CAE; Knoll, 1998).…”

Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion

“…In addition, deprenyl-induced TH enzyme may be favored by the increase of TH activity due to melatonin [7,31]. A third factor involved in melatonin-deprenyl synergy come from their effect to enhance gene expression of glial cell line-derived neurotrophic factor [54], which in turn protects nigrostriatal pathway against MPTP [45].…”