Protection by GDNF and Other Trophic Factors Against the Dopamine‐Depleting Effects of Neurotoxic Doses of Methamphetamine

Abstract

Repeated methamphetamine (METH) administration to animals can result in long-lasting decreases in striatal dopamine (DA) content. It has previously been shown that glial cell line-derived neurotrophic factor (GDNF) can reduce the DA-depleting effects of neurotoxic doses of METH. However, there are several other trophic factors that are protective against dopaminergic toxins. Thus, the present experiments further investigated the protective effect of GDNF as well as the protective effects of several other trophic factors. Male Fischer-344 rats were given an intracerebral injection of trophic factor (2-10 microg) 1 day before METH (5 mg/kg, s.c., 4 injections at 2-h intervals). Seven days later DA levels in the striatum were measured using high-performance liquid chromatography (HPLC). Initial experiments indicated that only intrastriatal GDNF, and not intranigral GDNF, was protective. Thereafter, all other trophic factors were administered into the striatum. Members of the GDNF family (GDNF, neurturin, and artemin) all provided significant protection against the DA-depleting effects of METH, with GDNF providing the greatest protection. Brain-derived neurotrophic factor, neurotrophin-3, acidic fibroblast growth factor, basic fibroblast growth factor, ciliary neurotrophic factor, transforming growth factor-alpha (TGF-alpha), heregulin beta1 (HRG-beta1), and amphiregulin (AR) provided no significant protection at the doses examined. These results suggest that the GDNF family of trophic factors can provide significant protection against the DA-depleting effects of neurotoxic doses of METH.

The TrkB-Positive Dopaminergic Neurons are Less Sensitive to MPTP Insult in the Substantia Nigra of Adult C57/BL Mice

“…Reduced neurotrophic support or deficiency in neurotrophin production might be involved in the pathogenesis of PD, proposing a notion that additional supplement of neurotrophic factors rescue the dopaminergic neurons and exhibit protective role in PD by halting or reversing degenerative processes. GDNF is one recommended among neurotrophic factor that plays an important role in survival of dopaminergic neurons, and many studies have suggested its beneficial effect in therapeutic treatment of PD patients [5,12,49]. In animal models of PD, neurotrophic factors prevented neurodegeneration and improved behavioral recovery.…”

Dose-Dependent Effects of Binge-Like Methamphetamine Dosing on Dopamine and Neurotrophin Levels in Rat Brain

“…It has been shown to attenuate the dopamine depletion promoted by methamphetamine when administered 1 day in advance [56]. In addition to GDNF, other members of the GDNF family, neurturin and artemin, when injected into the striatum 1 day before methamphetamine, were also found to protect the rat brain against methamphetamine-induced depletion of dopamine [20,57]. We observed an overall main effect of methamphetamine on GDNF expression in the frontal cortex and striatum, but the post hoc analysis did not demonstrate significant differences from the effect in the controls.…”

“…GDNF activates several signalling cascades responsible for the regulation of cell survival, differentiation, proliferation, neurite outgrowth, and synaptic plasticity via the GDNF family receptor-α1 (GFR-α1) that can signal through RET [18]. Like BDNF, GDNF has been shown to protect rat dopaminergic neurons, e.g., against 6-hydroxydopamine toxicity [19], and intracerebral GDNF administration has been shown to reduce the dopamine-depleting effects of neurotoxic doses of methamphetamine in rats [20]. …”

Neurotrophic factors for the treatment of Parkinson's disease

“…This factor also has trophic effects on motor neurones [96] and has not been extensively investigated for its clinical potential in PD. The fourth member of the GFL family, artemin, has survivalpromoting effects on dopaminergic neurones in culture [98] and in vivo [99], and also has potent actions on sensory neurones of the dorsal root ganglia [98]. Like persephin, artemin has not progressed into clinical trials for PD; however it has been tested as a therapeutic for neuropathy [100].…”