Adenosine A2A receptor antagonist treatment of Parkinson’s disease

Adenosine A2A receptors have a unique cellular and regional distribution in the basal ganglia (BG), being particularly concentrated in areas richly innervated by dopamine (DA) such as the caudateputamen, otherwise called striatum, and the globus pallidus. Adenosine A2A and DA D2 receptors are capable of forming functional heteromeric complexes and are colocalised in striatopallidal neurons. Based on the peculiar cellular and regional distribution of this receptor and in line with data showing that A2A receptor antagonists improve motor symptoms of Parkinson’s disease (PD) in animal models and in clinical trials, A2A receptor antagonists have emerged as an attractive nondopaminergic target to improve the motor deficits that characterise PD. Experimental data have also shown that A2A receptor antagonists are capable of exerting a neuroprotective effect and do not induce neuroplasticity phenomena that complicate long-term dopaminergic treatments. The present review will provide an updated summary of results reported in the literature concerning the biochemical characteristics and BG distribution of A2A receptors. We subsequently aim to examine the effects of adenosine A2A antagonists in rodent and primate models of PD and L-DOPA-induced dyskinesia. Finally, conclusive remarks will be made on the neuroprotective effects of A2A antagonists and on the translation of adenosine A2A receptor antagonists in the treatment of PD.peer-reviewe

Adenosine A2A receptor antagonist treatment of Parkinson’s disease

Adenosine A2A receptors have a unique cellular and regional distribution in the basal ganglia (BG), being particularly concentrated in areas richly innervated by dopamine (DA) such as the caudateputamen, otherwise called striatum, and the globus pallidus. Adenosine A2A and DA D2 receptors are capable of forming functional heteromeric complexes and are colocalised in striatopallidal neurons. Based on the peculiar cellular and regional distribution of this receptor and in line with data showing that A2A receptor antagonists improve motor symptoms of Parkinson’s disease (PD) in animal models and in clinical trials, A2A receptor antagonists have emerged as an attractive nondopaminergic target to improve the motor deficits that characterise PD. Experimental data have also shown that A2A receptor antagonists are capable of exerting a neuroprotective effect and do not induce neuroplasticity phenomena that complicate long-term dopaminergic treatments. The present review will provide an updated summary of results reported in the literature concerning the biochemical characteristics and BG distribution of A2A receptors. We subsequently aim to examine the effects of adenosine A2A antagonists in rodent and primate models of PD and L-DOPA-induced dyskinesia. Finally, conclusive remarks will be made on the neuroprotective effects of A2A antagonists and on the translation of adenosine A2A receptor antagonists in the treatment of PD.peer-reviewe

Comics and studies on brain functions

The important role of Comics, in communication related to popular contexts and with people of all ages is undoubted. The meaning of comics goes beyond the pure representation of an image with a text, and this is one of the reasons why Comics have been used, in some instances, to study brain functions related to emotions, humourappreciation, image comprehension and visual language. In the past 20 years, the availability of instruments that could measure the activity of the brain in vivohas allowed us to develop experimental paradigms aimed at exploring the neural changes related not only to simple behaviours but also to increasingly complex functions such as emotions and consciousness [...

Role of movement in long-term basal ganglia changes: implications for abnormal motor responses

Abnormal involuntary movements (AIMs) and dyskinesias elicited by drugs that stimulate dopamine receptors in the basal ganglia are a major issue in the management of Parkinson’s disease (PD). Preclinical studies in dopamine-denervated animals have contributed to the modeling of these abnormal movements, but the precise neurochemical and functional mechanisms underlying these untoward effects are still elusive. It has recently been suggested that the performance of movement may itself promote the later emergence of drug-induced motor complications, by favoring the generation of aberrant motor memories in the dopamine-denervated basal ganglia. Our recent results from hemiparkinsonian rats subjected to the priming model of dopaminergic stimulation are in agreement with this. These results demonstrate that early performance of movement is crucial for the manifestation of sensitized rotational behavior, indicative of an abnormal motor response, and neurochemical modifications in selected striatal neurons following a dopaminergic challenge. Building on this evidence, this paper discusses the possible role of movement performance in drug-induced motor complications, with a look at the implications for PD management

A2A Receptor Antagonism and Dyskinesia in Parkinson's Disease

Dyskinesia, a major complication of treatment of Parkinson's disease (PD), involves two phases: induction, which is responsible for dyskinesia onset, and expression, which underlies its clinical manifestation. The unique cellular and regional distribution of adenosine A2A receptors in basal ganglia areas that are richly innervated by dopamine, and their antagonistic role towards dopamine receptor stimulation, have positioned A2A receptor antagonists as an attractive nondopaminergic target to improve the motor deficits that characterize PD. In this paper, we describe the biochemical characteristics of A2A receptors and the effects of adenosine A2A antagonists in rodent and primate models of PD on L-DOPA-induced dyskinesia, together with relevant biomarker studies. We also review clinical trials of A2A antagonists as adjuncts to L-DOPA in PD patients with motor fluctuations. These studies have generally demonstrated that the addition of an A2A antagonist to a stable L-DOPA regimen reduces OFF time and mildly increases dyskinesia. However, limited clinical data suggest that the addition of an A2A antagonist along with a reduction of L-DOPA might maintain anti-Parkinsonian benefit and reduce dyskinesia. Whether A2A antagonists might reduce the development of dyskinesia has not yet been tested clinically

Intensive Rehabilitation Treatment in Parkinsonian Patients with Dyskinesias: A Preliminary Study with 6-Month Followup

A major adverse effect of levodopa therapy is the development of dyskinesia, which affects 30–40% of chronically treated Parkinsonian patients. We hypothesized that our rehabilitation protocol might allow a reduction in levodopa dosage without worsening motor performances, thus reducing frequency and severity of dyskinesias. Ten Parkinsonian patients underwent a 4-week intensive rehabilitation treatment (IRT). Patients were evaluated at baseline, at the end of the rehabilitation treatment and at 6-month followup. Outcome measures were the Unified Parkinson's Disease Rating Scale Sections II, III, and IV (UPDRS II, III, IV) and the Abnormal Involuntary Movement Scale (AIMS). At the end of the IRT, levodopa dosage was significantly reduced (P = 0.0035), passing from 1016 ± 327 to 777 ± 333 mg/day. All outcome variables improved significantly (P < 0.0005 all) by the end of IRT. At followup, all variables still maintained better values with respect to admission (P < 0.02 all). In particular AIMS score improved passing from 11.90 ± 6.5 at admission to 3.10 ± 2.3 at discharge and to 4.20 ± 2.7 at followup. Our results suggest that it is possible to act on dyskinesias in Parkinsonian patients with properly designed rehabilitation protocols. Intensive rehabilitation treatment, whose acute beneficial effects are maintained over time, might be considered a valid noninvasive therapeutic support for Parkinsonian patients suffering from diskinesia, allowing a reduction in drugs dosage and related adverse effects

D2R signaling in striatal spiny neurons modulates L-DOPA induced dyskinesia

Degeneration of dopaminergic neurons leads to Parkinson's disease (PD), characterized by reduced levels of striatal dopamine (DA) and impaired voluntary movements. DA replacement is achieved by levodopa treatment which in long-term causes involuntary movements or dyskinesia. Dyskinesia is linked to the pulsatile activation of D1 receptors of the striatal medium spiny neurons (MSNs) forming the direct output pathway (dMSNs). The contribution of DA stimulation of D2R in MSNs of the indirect pathway (iMSNs) is less clear. Using the 6-hydroxydopamine model of PD, here we show that loss of DA-mediated inhibition of these neurons intensifies levodopa-induced dyskinesia (LID) leading to reprogramming of striatal gene expression. We propose that the motor impairments characteristic of PD and of its therapy are critically dependent on D2R-mediated iMSNs activity. D2R signaling not only filters inputs to the striatum but also indirectly regulates dMSNs mediated responses

Modulation of Rat 50-kHz Ultrasonic Vocalizations by Glucocorticoid Signaling: Possible Relevance to Reward and Motivation

BACKGROUND: Rats emit 50-kHz ultrasonic vocalizations (USVs) to communicate positive emotional states, and these USVs are increasingly being investigated in preclinical studies on reward and motivation. Although it is the activation of dopamine receptors that initiates the emission of 50-kHz USVs, non-dopaminergic mechanisms may modulate calling in the 50 kHz frequency band. To further elucidate these mechanisms, the present study investigated whether the pharmacological manipulation of glucocorticoid signaling influenced calling. METHODS: Rats were administered corticosterone (1-5 mg/kg, s.c.), the glucocorticoid receptor antagonist mifepristone (40 or 100 mg/kg, s.c.), or the corticosterone synthesis inhibitor metyrapone (50 or 100 mg/kg, i.p.). The effects of these drugs on calling initiation and on calling recorded during non-aggressive social contacts or after the administration of amphetamine (0.25 or 1 mg/kg, i.p.) were then evaluated. RESULTS: Corticosterone failed to initiate the emission of 50-kHz USVs and did not influence pro-social and amphetamine-stimulated calling. Similarly, mifepristone and metyrapone did not initiate calling. However, metyrapone suppressed pro-social calling and calling stimulated by a moderate dose (1 mg/kg, i.p.) of amphetamine. Conversely, mifepristone attenuated calling stimulated by a low (0.25 mg/kg, i.p.), but not moderate (1 mg/kg, i.p.), dose of amphetamine, and had no influence on pro-social calling. CONCLUSIONS: The present results demonstrate that glucocorticoid signaling modulates calling in the 50 kHz frequency band only in certain conditions, and suggest that mechanisms different from the inhibition of corticosterone synthesis may participate in the suppression of calling by metyrapone

Novel (Hetero)arylalkenyl propargylamine compounds are protective in toxin-induced models of Parkinson's disease

Background: Mitochondrial dysfunction, oxidative stress and their interplay are core pathological features of Parkinson's disease. In dopaminergic neurons, monoamines and their metabolites provide an additional source of reactive free radicals during their breakdown by monoamine oxidase or auto-oxidation. Moreover, mitochondrial dysfunction and oxidative stress have a supraadditive impact on the pathological, cytoplasmic accumulation of dopamine and its subsequent release. Here we report the effects of a novel series of potent and selective MAO-B inhibitory (hetero)arylalkenylpropargylamine compounds having protective properties against the supraadditive effect of mitochondrial dysfunction and oxidative stress. Results: The (hetero)arylalkenylpropargylamines were tested in vitro, on acute rat striatal slices, pretreated with the complex I inhibitor rotenone and in vivo, using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced acute, subchronic, and chronic experimental models of Parkinson's disease in mice. The compounds exhibited consistent protective effects against i) in vitro oxidative stress induced pathological dopamine release and the formation of toxic dopamine quinone in the rat striatum and rescued tyrosine hydroxylase positive neurons in the substantia nigra after rotenone treatment; ii) in vivo MPTP-induced striatal dopamine depletion and motor dysfunction in mice using acute and subchronic, delayed application protocols. One compound (SZV558) was also examined and proved to be protective in a chronic mouse model of MPTP plus probenecid (MPTPp) administration, which induces a progressive loss of nigrostriatal dopaminergic neurons. Conclusions: Simultaneous inhibition of MAO-B and oxidative stress induced pathological dopamine release by the novel propargylamines is protective in animal models and seems a plausible strategy to combat Parkinson's disease

Decreased Rhes mRNA levels in the brain of patients with Parkinson's disease and MPTP-treated macaques

In rodent and human brains, the small GTP-binding protein Rhes is highly expressed in virtually all dopaminoceptive striatal GABAergic medium spiny neurons, as well as in large aspiny cholinergic interneurons, where it is thought to modulate dopamine-dependent signaling. Consistent with this knowledge, and considering that dopaminergic neurotransmission is altered in neurological and psychiatric disorders, here we sought to investigate whether Rhes mRNA expression is altered in brain regions of patients with Parkinsonâ\u80\u99s disease (PD), Schizophrenia (SCZ), and Bipolar Disorder (BD), when compared to healthy controls (about 200 post-mortem samples). Moreover, we performed the same analysis in the putamen of non-human primate Macaca Mulatta, lesioned with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Overall, our data indicated comparable Rhes mRNA levels in the brain of patients with SCZ and BD, and their respective healthy controls. In sharp contrast, the putamen of patients suffering from PD showed a significant 35% reduction of this transcript, compared to healthy subjects. Interestingly, in line with observations obtained in humans, we found 27% decrease in Rhes mRNA levels in the putamen of MPTP-treated primates. Based on the established inhibitory influence of Rhes on dopamine-related responses, we hypothesize that its striatal downregulation in PD patients and animal models of PD might represent an adaptive event of the dopaminergic system to functionally counteract the reduced nigrostriatal innervation