Supra-nigral administration of an mGlu4 receptor allosteric potentiator protects against histological and functional deficits in the 6-OHDA lesion rat model of Parkinson’s disease

Matthew Betts1, Michael O’Neill2, Stephen Mitchell2, Susan Duty1. 1King’s College London, London, United Kingdom, 2Eli Lilly & Co Ltd., Windlesham,Surrey, United Kingdom.

Having previously shown that supranigral administration of the broad spectrum group III mGlu receptor agonist, L-AP4, provides histological and functional protection in the 6-hydroxydopamine (6-OHDA) lesion rat model of PD, we now probe involvement of mGlu4 receptors in this response using the mGlu4 positive allosteric modulator, VU0155051 (cis-2-(3,5-dichlorophenylcarbocamoyl) cyclohexanecarboxylic acid) (Niswender et al., 2008).

Under isofluorane general anaesthesia, male Sprague Dawley rats (270-290g) were cannulated 2 mm above the right substantia nigra pars compacta (SNpc). One week later, supranigral injections of VU0155041 (10 -100nmol in 4 μl PBS) or vehicle were given 1h before and daily for 7 days after an intranigral 6-OHDA injection (6 μg in 2.5 μl). Motor function was assessed pre- (day 0) and post-lesion using the cylinder reaching test (day 0 and 4), the adjusted steps test (day 0 and 6) and amphetamine (5 mg kg-1 i.p.)-induced rotation test (day 7). On day 8, animals were perfuse fixed under terminal anaesthesia, the brains removed and processed for tyrosine hydroxylase (TH) immunohistochemistry in striatum and SNpc and for HPLC measurement of striatal dopamine content. Data are expressed as mean ± s.e. mean; n = 11 (vehicle treatment group) or n = 6 (VU0155041 treatment groups) and comparisons made using 1-or 2-way ANOVA and Bonferroni’s post-hoc test (P< 0.05).

The adjusted steps test revealed a deficit in contralateral paw use in lesioned animals treated with vehicle (49.7 ± 7.7% of pre-lesion score) which was significantly spared in animals treated with 100nmol VU0155041 (90.9 ± 13.5% of pre-lesion). VU0155041 also improved contralateral paw use in the cylinder test and reduced amphetamine-induced rotations although failing to reach significance. TH levels in the lesioned striatum fell to 9.6 ± 3.6% of intact side in vehicle-treated animals, whilst in 100 nmol VU0155041-treated animals TH remained at 43.8 ± 5.7% of intact side. Significant protection against loss of TH-positive cells in the SNpc and of striatal dopamine content was also seen with VU0155041 treatment.

These data reveal that activation of mGlu4 receptors in the SNpc offers protection against histological, neurochemical and behavioural deficits produced by nigrostriatal tract lesion and support further studies into the potential of targeting mGlu4 receptors for treating PD.

Niswender CM et al. (2008). Mol Pharmacol 74: 1345-1358.