The combination of oral L-DOPA/rimonabant for effective dyskinesia treatment and cytological preservation in a rat model of Parkinson’s disease and L-DOPA-induced dyskinesia

Abstract

Parkinson's disease is the second most prevalent neurodegenerative disease in the world. Its treatment is limited so far to the management of parkinsonian symptoms with L-DOPA (LD). The long-term use of LD is limited by the development of L-DOPA-induced dyskinesias and dystonia. However, recent studies have suggested that pharmacological targeting of the endocannabinoid system may potentially provide a valuable therapeutic tool to suppress these motor alterations. In the present study, we have explored the behavioral (L-DOPA-induced dyskinesias severity) and cytological (substantia nigra compacta neurons and striatum neuropil preservation) effects of the oral coadministration of LD and rimonabant, a selective antagonist of CB1 receptors, in the 6-hydroxydopamine rat model of Parkinson's disease. Oral coadministration of LD (30 mg/kg) and rimonabant (1 mg/kg) significantly decreased abnormal involuntary movements and dystonia, possibly through the conservation of some functional tyrosine hydroxylase-immunoreactive dopaminergic cells, which in turn translates into a well-preserved neuropil of a less denervated striatum. Our results provide anatomical evidence that long-term coadministration of LD with cannabinoid antagonist-based therapy may not only alleviate specific motor symptoms but also delay/arrest the degeneration of striatal and substantia nigra compacta cells.

The bright side of psychoactive substances: cannabinoid-based drugs in motor diseases

“…As shown in MPTP-treated marmosets, SR 141716A administration can improve motor function and reduce L-DOPA-induced dyskinesia [46]. Similar findings were described later in the 6-OHDA rat model of PD in which the co-administration of SR 141716A and L-DOPA reduced the AIMs elicited by repeated L-DOPA treatment also exerting some anti-degenerative effects in terms of preservation of DAergic nigral cells [47]. This study provides an interesting therapeutic perspective in which CB 1 receptor blockade parallels, and not follows, L-DOPA treatment and therefore might prevent the development of the AIMs.…”

“…Another stimulating therapeutic field for the investigation of cannabinoid-based drugs is offered by the anti-dyskinetic potential for the clinical management of PD-associated motor symptoms [46,47]. We believe that cannabinoid-based drugs possess a great therapeutic potential that There are nonetheless specific clues that should be followed within a short-term perspective.…”

Cannabinoid–dopamine interactions in the physiology and physiopathology of the basal ganglia

“…On the other hand, another conflicting result derived from studies showing that CB 1 receptor antagonists also reduced and/or delayed levodopa‐induced dyskinesia (see Fabbrini et al ., ). Their administration in combination with levodopa produces some interesting synergies in relation with motor symptoms but also with disease progression (Gutiérrez‐Valdez et al ., ). Again, this indicates the complexity of the neuronal circuitry in which both CB 1 agonists and antagonists may provide the same type of therapeutic benefit, a fact presumably related to the presence of these receptors in both excitatory and inhibitory synapses within the basal ganglia circuitry.…”

Coadministration of hydroxysafflor yellow A with levodopa attenuates the dyskinesia

“…Coadministration of l-stepholidine (one of the active ingredients of the Chinese herb Stephania intermedia) with L-DOPA significantly ameliorated LID without compromising the therapeutic potency of L-DOPA [5]. Previous study showed that oral coadministration of L-DOPA and rimonabant significantly decreased abnormal involuntary movements and dystonia [6]. Acupuncture and L-DOPA combination therapy reduces the effective dose of L-DOPA and alleviates LID [7].…”