Adenosine A_2A receptor antagonists improve deficits in initiation of movement and sensory motor integration in the unilateral 6‐hydroxydopamine rat model of Parkinson's disease

Abstract

Evidence obtained in rodent and primate models of Parkinson's disease (PD) and preliminary clinical trials, indicates that adenosine A(2A) receptor antagonists might represent a promising nondopaminergic therapeutic tool for the treatment of PD. Those studies demonstrated the ability of adenosine A(2A) receptor antagonists to potentiate l-dopa-mediated motor improvement, whereas very little is known about counteraction of specific motor deficits and on the effects of these compounds when administered alone. To this aim we evaluated the effects of different adenosine A(2A) receptor antagonists on initiation of movement deficits, gait impairment and sensory-motor deficits, induced in rats by a unilateral 6-hydroxydopamine lesion of dopaminergic nigrostriatal neurons. The following tests were used: (1) initiation time of stepping; (2) adjusting step (stepping with forelimb was measured as the forelimb was dragged laterally); (3) vibrissae-elicited forelimb placing (as index of sensory-motor integration deficits). Acute administration of the A(2A) receptor antagonists SCH 58261 (5 mg/kg i.p.) and ST 1535 (20 mg/kg i.p.) similarly to l-dopa (6 mg/kg i.p.) counteracted the impairments in the initiation time of stepping test, in the adjusting step and in the vibrissae-elicited forelimb placing induced by the lesion. The intensity of the effect was l-dopa > SCH 58261 > ST 1535. The results provide the first evidence that blockade of A(2A) receptors is effective in antagonizing specific motor deficit induced by DA neuron degeneration, such as initiation of movement and sensory-motor integration deficits, even without l-dopa combined administration.

Adenosine A2A Receptor Antagonists as Drugs for Symptomatic Control of Parkinson’s Disease in Preclinical Studies

“…A few A 2A receptor antagonists, similarly to L-DOPA completely restored placement of the contralateral forelimb by rats, with different intensity depending on the different A 2A receptor antagonists tested, suggesting a potential efficacy of these compounds to ameliorate the sensorimotor integration deficits in PD patients (Table 7.1 and Fig. 7.2; Pinna and Morelli 2014;Pinna et al 2007Pinna et al , 2010. This effect was not due to spontaneous recovery of sensorimotor integration deficits by hemiparkinsonian rats (Pinna and Morelli 2014;Pinna et al 2007Pinna et al , 2010.…”

“…7.2; Pinna et al 2007Pinna et al , 2010Pinna and Morelli 2014). Notably, hemiparkinsonian rats did not show any spontaneous recovery in the adjusting test and in initiation time in the stepping test during the period in which the drug test was performed (Pinna et al 2007(Pinna et al , 2010.…”

“…Administration of the A 2A receptor antagonists, similarly to L-DOPA significantly counteracted forelimb akinesia/hypokinesia and motor initiation deficit, as demonstrated by their effect in increasing the number of steps performed in both a forward and backward direction and in improving initiation time of stepping by the forelimb contralateral to the lesion, with different intensity, depending on the A 2A receptor antagonists tested (Table 7.1 and Fig. 7.2; Pinna et al 2007Pinna et al , 2010Pinna and Morelli 2014). Notably, hemiparkinsonian rats did not show any spontaneous recovery in the adjusting test and in initiation time in the stepping test during the period in which the drug test was performed (Pinna et al 2007(Pinna et al , 2010.…”

“…Indeed, hemiparkinsonian rats made less steps with the forelimb contralateral to the lesion, compared with their ipsilateral forelimb, showing a marked reduction of movements defined as hypokinesia (Chang et al 1999;Olsson et al 1995;Pinna et al 2007Pinna et al , 2010. Moreover, hemiparkinsonian rats show marked and long-lasting impairment in the initiation time of stepping movement of the contralateral to the lesioned side, an impairment considered to be of symptomatic validity for the initiation of movement deficit present in parkinsonian patients (Meredith and Kang 2006;Olsson et al 1995;Pinna et al 2007Pinna et al , 2010. Both deficits described were effectively counteracted by a dose of L-DOPA at sub-threshold levels for induction of rotation.…”

“…These sensorimotor deficits, assessed by means of the vibrissae-elicited forelimb placing test, hampered the hemiparkinsonian rats when placing their forelimb contralateral to the lesion on the table surface after brushing of the vibrissae on the same side, whereas the ipsilateral forelimb was not affected by the lesion (Meredith and Kang 2006;Pinna et al 2007Pinna et al , 2010Schallert et al 2000). A few A 2A receptor antagonists, similarly to L-DOPA completely restored placement of the contralateral forelimb by rats, with different intensity depending on the different A 2A receptor antagonists tested, suggesting a potential efficacy of these compounds to ameliorate the sensorimotor integration deficits in PD patients (Table 7.1 and Fig.…”