Pharmacological Activation of mGlu4 Metabotropic Glutamate Receptors Reduces Nigrostriatal Degeneration in Mice Treated with 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine

Abstract

We examined whether selective activation of mGlu4 metabotropic glutamate receptors attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal damage in mice. C57BL mice were treated with a single dose of MPTP (30 mg/kg, i.p.) preceded, 30 min earlier, by a systemic injection of the mGlu4 receptor enhancer N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC). PHCCC was injected either subcutaneously in cremophor EL or intraperitoneally in saline containing 50% DMSO. PHCCC treatment (3 or 10 mg/kg) significantly reduced MPTP toxicity, as assessed by measurements of the striatal levels of dopamine and its metabolites and by tyrosine hydroxylase, dopamine transporter, and glial fibrillary acidic protein immunostaining in the corpus striatum and substantia nigra. In another set of experiments, a higher cumulative dose of MPTP (80 mg/kg divided into four injections with 2 h of interval) was injected to mGlu4 Ϫ/Ϫ mice and their Sv129/CD1 wild-type controls. A higher dose was used in these experiments because Sv129/CD1 mice are less sensitive to MPTP toxicity. Systemic administration of PHCCC was protective in wild-type mice but failed to affect nigrostriatal damage in mGlu4 Ϫ/Ϫ mice. Finally, unilateral infusion of PHCCC in the external globus pallidus protected the ipsilateral nigrostriatal pathway against MPTP toxicity. These data support the view that mGlu4 receptors are potential targets for the experimental treatment of parkinsonism.

Targeting Group III Metabotropic Glutamate Receptors Produces Complex Behavioral Effects in Rodent Models of Parkinson's Disease

“…havioral effects. Previous in vitro and ex vivo studies reported that a selective mGluR4 agonist induces neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity (Battaglia et al, 2006) and potentiates L-AP4-induced inhibition at striatopallidal synapse, whereas the mGluR8 agonist DCPG had no effect Valenti et al, 2003). In line with this, our results favor mGluR4-mediated effects at GP level because DCPG did not reverse haloperidol-induced catalepsy.…”

Selective Activation of Group III Metabotropic Glutamate Receptors by l-(+)-2-Amino-4-phosphonobutryic Acid Protects the Nigrostriatal System against 6-Hydroxydopamine Toxicity in Vivo

“…This is interesting since the use of direct mGluR agonists like L-AP4 as a chronic treatment for PD is likely to be limited by adverse effects associated with excessive activation of the receptor, including receptor desensitization and loss of the neuronal activity dependence of receptor activation by pulsatile release of neurotransmitter (Conn, 2003). In conclusion, the findings presented herein, together with complementary data published during the course of the present study suggesting that the mGluR4-selective positive allosteric modulator PHCCC is neuroprotective against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced nigrostriatal damage in mice (Battaglia et al, 2006), provide compelling evidence that selective activation of Group III mGluR is neuroprotective in vivo in experimental models of parkinsonism, which may have implications for the future treatment of PD. …”

Pharmacological Activation of mGlu4 Metabotropic Glutamate Receptors Inhibits the Growth of Medulloblastomas

“…The drug was either injected systemically (5 mg/kg, s.c.) or infused intracranially in the cerebellar region (10 nmol/0.5 l). We expect that subcutaneously injected PHCCC at doses of 5 mg/kg can penetrate the brain because it can reverse reserpine-induced bradykinesia in mice (Battaglia et al, 2006). Control Ptc neo67/ϩ mice treated subcutaneously or intracranially with vehicle during the first 8 d of life showed the expected incidence of medulloblastomas (85-90%) when autopsied after 10 weeks (Fig.…”