A mGluR5 antagonist under clinical development improves L-DOPA-induced dyskinesia in parkinsonian rats and monkeys
Introduction
The striatum is densely innervated by dopaminergic (DA) fibers from the substantia nigra and glutamatergic afferents from all parts of the cortex (Gerfen, 1992). Both dopamine (DA) and glutamate play major roles in the pathophysiology of Parkinson's disease (PD) (Calabresi et al., 2007, Chase and Oh, 2000). Loss of nigrostriatal DA fibers causes the main motor features of PD (Morrish et al., 1996) which can be pharmacologically treated with the DA precursor, L-DOPA. The medication remains the most effective treatment for PD but causes motor fluctuations and dyskinesia (abnormal involuntary movements) in up to 80% of the patients after a few years of treatment (Fabbrini et al., 2007). In both patients and animal models, L-DOPA-induced dyskinesia (LID) has been associated with plastic changes in pre-synaptic as well as post-synaptic neuronal targets in the striatum, including abnormal activation of key signaling kinases (Bezard et al., 2005, Picconi et al., 2003, Santini et al., 2007, Westin et al., 2007), elevated extracellular levels of glutamate (Robelet et al., 2004) and DA (Lindgren et al., 2010), and abnormal intracellular trafficking of DA and glutamate receptor subunits (Berthet and Bezard, 2009, Chase et al., 2000, Gardoni et al., 2006, Hallett et al., 2005, Silverdale et al., 2010). All these changes point to dysfunctional interactions between DA and glutamate neurotransmission in LID (Cenci and Lindgren, 2007, Cenci and Lundblad, 2006, Chase et al., 2000). Because antagonism of DA receptors may worsen PD motor symptoms, several glutamate receptor antagonists, especially of the ionotropic type, have been proposed for a pharmacological treatment of LID (Fox et al., 2006). Antagonists of ionotropic receptors may, however, induce cognitive and psychiatric impairments (Meldrum, 1998). Metabotropic glutamate receptors (mGluR) have received growing attention as potential targets for anti-parkinsonian and antidyskinetic treatments (Conn et al., 2005, Marino and Conn, 2006). Ligands to these receptors can normalize excessive glutamate transmission without blocking the physiological actions of glutamate in the brain (Rouse et al., 2000). Of particular interests is metabotropic glutamate receptor 5 (mGluR5), a G-protein coupled receptor that is positively linked to phosphoinositide hydrolysis (group I mGluRs) (Pin and Duvoisin, 1995). This receptor is highly expressed in striatal medium spiny neurons (Testa et al., 1994) where it plays a key role in modulating the responses mediated by NMDA receptors and L-type calcium channels (reviewed in Gubellini et al., 2004). We have previously shown that the selective mGluR5 antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), can reduce the severity of LID and inhibit the associated molecular and neurochemical changes in rats with 6-hydroxydopamine (6-OHDA) lesions (Dekundy et al., 2006, Mela et al., 2007, Rylander et al., 2009). However, MTEP has no translational potential. We therefore searched for another mGluR5 antagonist, amenable to clinical use, in order to conduct a comprehensive preclinical validation of the mGluR5 target. Fenobam was under development already in the 1970s as non-benzodiazepine anxiolytic compound with potentially good safety profile (Pecknold et al., 1982) but was first identified as a potent, non-competitive mGluR5 antagonist in 2005 (Porter et al., 2005). It shares the same allosteric modulatory site as the prototypical mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP) (Gasparini et al., 1999) and, similar to MPEP, it is a candidate compound for the treatment of fragile X syndrome as well as pain (Berry-Kravis et al., 2009, Jacob et al., 2009, Montana et al., 2009). This study provides evidence of anti-dyskinetic and anti-akinetic effects of fenobam in two well-established animal models of PD. With its favourable profile of motor effects and its amenability to clinical use, fenobam can be regarded as a candidate treatment for motor complications in PD.
Section snippets
Animals
For the rat experiments, female Sprague–Dawley rats (Harlan, Netherlands), weighing 225–250 g at the beginning of the study were used. They were house in a 12 h dark–light cycle and had food and water ad libitum. All the procedures were approved by the Malmö-Lund ethical committee on animal research.
Non-human primate models of PD and LID were produced in male rhesus monkeys (Macaca mulatta, Xierxin, Beijing, PR of China; mean weight = 5.3 ± 0.8 kg; mean age = 5 ± 1 years) as in (Aubert et al., 2005).
Fenobam reduces already established LID and prolongs the effect of L-DOPA in the rat
In severely dyskinetic rats (n = 14), both doses of fenobam (30 mg/kg and 100 mg/kg) reduced the axial, limb, and orolingual AIM scores by approximately 50% up to 80 min following the administration of L-DOPA, corresponding to the beginning and the peak of the LID curve (Fig. 1A, repeated measures ANOVA, group effect: F(2,351) = 0.941, p = 0.398; time effect: F(9,351) = 46.318, p < 0.001; interaction: F(18,351) = 4.257, p < 0.001 and B, one-factor ANOVA, treatment effect: F(13,26) = 14.84, p < 0.001). When
Discussion
An overactive glutamate transmission plays an important role in PD, contributing both to the degeneration of DA neurons and to maladaptive plasticity and altered synaptic transmission in dopaminoceptive structures (for review see: Bezard et al., 2001a, Cenci and Lindgren, 2007; Chase et al., 2000, Fox et al., 2008, Miller et al., 1995).
Metabotropic glutamate receptor 5 is highly expressed post-synaptically on striatal medium spiny neurons and interneurons (Testa et al., 1994) where it plays a
Acknowledgments
This study was supported by grants from the Michael J. Fox Foundation for Parkinson's Research (MAC and EB), and from the Swedish National Research Council and European Community [Contract 222918] (MAC).
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