Experimental studies in animals have demonstrated excessive glutamatergic transmission as a key factor contributing to the pathophysiology of L-dopa induced dyskinesias (LIDs) in Parkinson's Disease (PD) (Suppa et al., 2017a). In a recent transcranial magnetic stimulation (TMS) study, we have demonstrated abnormal facilitation of the primary motor cortex (M1), in patients with PD and LIDs (Guerra et al., 2019). More in detail, the enhanced M1 facilitation in patients with LIDs was reflected by abnormally increased short-interval intracortical facilitation (SICF), an indirect measure of glutamatergic activity in M1, in patients with PD and LIDs. We also demonstrated that one month of chronic treatment with safinamide, a currently available drug for PD with dopaminergic (MAO-B inhibitor) and anti-glutamatergic properties, restored SICF and prevented LIDs worsening owing to a "short-term" effect (Guerra et al., 2019). These findings suggest a pathophysiological link between abnormal SICF and overactive glutamatergic transmission in M1, in agreement with the classical model of LIDs pathophysiology.
In this study, we will investigate the "long-term" effects of safinamide in patients with PD and LIDs, by testing several clinical and neurophysiological measures (e.g. SICF), after 12-month of chronic treatment. A total of 20 patients with PD and LID will participate at 3 experimental sessions: 1) baseline (without safinamide); 2) safinamide (14 days) and; 3) safinamide (12 months). We will examine possible changes in clinical motor symptoms, including LIDs and SICF following 12-month of chronic treatment with safinamide. In addition to SICF, the neurophysiological study will also include the examination of possible long-term changes in M1 synaptic plasticity. To this aim, in all sessions, we will also examine long-term changes in motor evoked potential amplitudes induced by the standardized intermittent theta-burst stimulation (iTBS) protocol (Suppa et al., 2016).
The clinical management of patients with PD is complicated by the chronic use of L-dopa which leads to motor fluctuations characterized by wearing-off phenomena, unpredictable deterioration of motor symptoms (OFF) and (LIDs). Previous randomized controlled studies have shown that Safinamide may improve motor fluctuations without causing worsening of LIDs. In vivo and in vitro studies have disclosed that the mechanism of action of Safinamide involves both dopaminergic and non-dopaminergic transmission. Safinamide is a selective and reversible inhibitor of monoamine oxidase-B (MAO-B), a state- and frequency-dependent voltage-gated sodium (Na+) channel blocker, and an inhibitor of glutamate release in the synaptic space. Despite the available data obtained from in vivo and in vitro studies, little is known about the mechanisms (dopaminergic or non-dopaminergic) responsible for the clinical benefits produced by Safinamide in patients with PD. One hypothesis is that long-term inhibition of glutamate release induced by Safinamide at the primary motor cortex (M1) level might be an important factor in the clinical effects of the drug.
In a recent study (Guerra et al., 2019), we provided evidence that patients with PD, and particularly those with LIDs, have a significant increase of the Short-interval Intra-Cortical Facilitation (SICF). This abnormality, particularly evident in patients with LIDs, improved with Safinamide 50 mg/day and was normalized by Safinamide 100 mg/day. These data suggest the existence of a link between the anti-glutamatergic mechanism of action of Safinamide 100 mg and the pathophysiological mechanisms underlying the abnormal SICF in patients with PD and LIDs. We also showed a positive correlation between the effect of Safinamide 100 mg/day on SICF and the severity of LIDs, suggesting that the abnormal glutamatergic transmission in M1 is involved in the pathophysiology of LIDs.
We think that our experimental study based on clinical as well as neurophysiological thorough investigation will shed light on the pathophysiology of the altered cortical excitability and plasticity mechanisms underlying the human M1 in patients with Parkinson's Disease (PD) and L-dopa induced dyskinesias (LIDs). Indeed, we think that our study focusing on the long-lasting effects of chronic treatment with safinamide 100 mg/day will improve knowledge on the pathophysiology of motor fluctuations and dyskinesias in patients with PD and their relationship with the altered glutamatergic transmission in circuits underlying cortical facilitation in M1. The novelty of this proposal is that we will focus on clinical and neurophysiological measures to achieve a correlation that would be useful to develop neurophysiological markers of disease progression in patients with PD. Furthermore, for the first time, we will analyse mechanisms of synaptic plasticity of the human M1 in patients with PD and LIDs chronically treated with PD. To this aim we will administer to our patients with PD and LIDs, a repetitive TMS protocol based on the intermittent theta burst stimulation (iTBS), which is a non-invasive brain stimulation technique able to induce long-term potentiation- (LTP)-like plasticity in M1, outlasting the time of stimulation. It is known that the LTP-like plasticity of the human M1 is altered in patients with PD (Guerra et al., 2020), but the effect of chronic treatment with safinamide on this measure of synaptic plasticity has never be investigated.