Adenosine A2A Receptor Antagonist Istradefylline Research Articles

Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects.

Cisplatin is a potent chemotherapeutic drug that is widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, in particular nephrotoxicity and chemotherapy-induced peripheral neuropathy. Thus, there is an urgent medical need to identify novel strategies that limit cisplatin-induced toxicity. In the present study, we show that the FDA-approved adenosine A2A receptor antagonist istradefylline (KW6002) protected from cisplatin-induced nephrotoxicity and neuropathic pain in mice with or without tumors. Moreover, we also demonstrate that the antitumoral properties of cisplatin were not altered by istradefylline in tumor-bearing mice and could even be potentiated. Altogether, our results support the use of istradefylline as a valuable preventive approach for the clinical management of patients undergoing cisplatin treatment.

Characterization of the discriminative stimulus effect of quinpirole: Further evidence for functional interaction between central dopamine D1/D2-receptors

Dysfunction of the central dopamine D2-receptor-related network has been proposed to play a critical role in dopamine-related diseases, such as schizophrenia and drug dependence. Generally, the stimulation of dopamine D2-receptors on medium spiny neurons (MSN) induces several behavioral effects, such as sedation, hallucination, aversion and motivation. Furthermore, such physiological responses through dopamine D2-receptor-containing MSN (D2-MSN) may be synchronized with the activity of dopamine D1-receptor-containing MSN (D1-MSN), or both may exhibit dual agonistic/antagonistic innervation. In the present study, we characterized the discriminative stimulus effect of the selective dopamine D2-receptor agonist quinpirole to further investigate the “D1/D2-MSN” interaction using dopamine-related agents, hallucinogens and sedatives in rats. Among dopamine receptor agonists, only selective dopamine D2-receptor agonists substituted for the discriminative stimulus effects of quinpirole. Neither the δ-opioid receptor agonist SNC80 nor the adenosine A2A-receptor antagonist istradefylline, both of which may act on D2-MSNs, substituted for the discriminative stimulus effects of quinpirole. Interestingly, the dopamine D1-receptor antagonist SCH23390 and the GABAB-receptor agonist baclofen, but not hallucinogens or sedatives, substituted for the discriminative stimulus effects of quinpirole. These results suggest that stimulation of central dopamine D2-receptors exerts a distinct discriminative stimulus effect, and blockade of dopamine D1-receptors and agonistic modulation of GABAB-receptors may share the discriminative stimulus effect via the activation of central dopamine D2-receptors.

Ecto-NTPDase CD39 is a negative checkpoint that inhibits follicular helper cell generation.

Vaccination is a mainstay in preventive medicine, reducing morbidity and mortality from infection, largely by generating pathogen-specific neutralizing antibodies. However, standard immunization strategies are insufficient with increasing age due to immunological impediments, including defects in T follicular helper (Tfh) cells. Here, we found that Tfh generation is inversely linked to the expression of the ecto-NTPDase CD39 that modifies purinergic signaling. The lineage-determining transcription factor BCL6 inhibited CD39 expression, while increased Tfh frequencies were found in individuals with a germline polymorphism preventing transcription of ENTPD1, encoding CD39. In in vitro human and in vivo mouse studies, Tfh generation and germinal center responses were enhanced by reducing CD39 expression through the inhibition of the cAMP/PKA/p-CREB pathway, or by blocking adenosine signaling downstream of CD39 using the selective adenosine A2a receptor antagonist istradefylline. Thus, purinergic signaling in differentiating T cells can be targeted to improve vaccine responses, in particular in older individuals who have increased CD39 expression.

The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinson's disease.

After more than two decades of preclinical and clinical studies, on August 27, 2019, the US Food and Drug Administration (FDA) approved the adenosine A2A receptor antagonist Nourianz® (istradefylline) developed by Kyowa Hakko Kirin Inc., Japan, as an add-on treatment to levodopa in Parkinson's disease (PD) with "OFF" episodes. This milestone achievement is the culmination of the decade-long clinical studies of the effects of istradefylline in more than 4000 PD patients. Istradefylline is the first non-dopaminergic drug approved by FDA for PD in the last two decades. This approval also provides some important lessons to be remembered, namely, concerning disease-specific adenosine signaling and targeting subpopulation of PD patients. Importantly, this approval paves the way to foster entirely novel therapeutic opportunities for adenosine A2A receptor antagonists, such as neuroprotection or reversal of mood and cognitive deficits in PD and other neuropsychiatric diseases.

The effect of adenosine A2A receptor antagonist istradefylline on multiple organ dysfunction in heatstroke rats

Background: Global warming increases the incidence of heatstroke, which is the most severe heat illness. The mortality in patients with heatstroke is due to neurological disability and multiple organ failure caused by systemic inflammatory response. Adenosine A2A receptor antagonist has both neuroprotective and anti-inflammatory effects. Thus, we examined whether a new A2A receptor antagonist istradefylline has beneficial effects in heatstroke rats. Methods: Wistar rats were divided into four groups: (1) control group, with vehicle only (intravenous [iv] for 10 min); (2) control + istradefylline group, with 0.3 mg/kg istradefylline (iv for 10 min); (3) heatstroke group, rectal temperature reached 44.1°C, and then returned to room temperature with vehicle (iv for 10 min); and (4) heatstroke + istradefylline group, rectal temperature reached 44.1°C, and then returned to room temperature with 0.3 mg/kg istradefylline (iv for 10 min). During the experimental period, rectal temperature, heart rate, blood pressure, and pressor responses to norepinephrine (NE) were monitored. Before and after the rats were put into heating chamber, and after the rats returned to room temperature for 6 h, their blood was taken to analyze creatine kinase, lactate dehydrogenase, blood urea nitrogen, creatinine, alanine transaminase, albumin, total protein, and platelet count. In addition, the blood flow of tongue, left limb, and right limb was also monitored. Finally, we examined their survival rate. Results: In the present study, heatstroke rats showed high core body temperature accompanied with cardiac abnormalities and multiple organ dysfunction, mimicking the clinical manifestations of heatstroke patients. Treatment of heatstroke rats with istradefylline only partially improved platelet loss and vascular hyporeactivity to NE. However, istradefylline had no significant effects on cardiac abnormalities and multiple organ dysfunction in rats with heatstroke. Conclusions: These results suggest that although istradefylline has a mild impact on abnormal platelet count and pressor response to NE in heatstroke, both effects are unlikely to counteract multiple organ dysfunction and the mortality.

Istradefylline reduces memory deficits in aging mice with amyloid pathology

Adenosine A2A receptors are putative therapeutic targets for neurological disorders. The adenosine A2A receptor antagonist istradefylline is approved in Japan for Parkinson's disease and is being tested in clinical trials for this condition elsewhere. A2A receptors on neurons and astrocytes may contribute to Alzheimer's disease (AD) by impairing memory. However, it is not known whether istradefylline enhances cognitive function in aging animals with AD-like amyloid plaque pathology. Here, we show that elevated levels of Aβ, C-terminal fragments of the amyloid precursor protein (APP), or amyloid plaques, but not overexpression of APP per se, increase astrocytic A2A receptor levels in the hippocampus and neocortex of aging mice. Moreover, in amyloid plaque-bearing mice, low-dose istradefylline treatment enhanced spatial memory and habituation, supporting the conclusion that, within a well-defined dose range, A2A receptor blockers might help counteract memory problems in patients with Alzheimer's disease.

Effectivness of selective adenosine A2A receptor antagonist istradefylline on the motor symptoms of Parkinson’s disease correlates with the intracortical inhibition revealed by transcranial magnetic stimulation

Effectivness of selective adenosine A2A receptor antagonist istradefylline on the motor symptoms of Parkinson’s disease correlates with the intracortical inhibition revealed by transcranial magnetic stimulation

Efficacy of adenosine A2A receptor antagonist istradefylline as augmentation for Parkinson's disease: a meta-analysis of randomized controlled trials.

Adenosine A2A receptor antagonist istradefylline has been approved this year for manufacturing and marketing in Japan. We, therefore, did this meta-analysis to systematically assess the efficacy and safety of istradefylline as augmentation to levodopa in patients with Parkinson's disease (PD). We systematically review the relative randomized controlled trials (RCTs) up to March 2014, which compared istradefylline to placebo for the short course of treatment for PD in adults. The primary outcome was daily OFF time and secondary outcome was UPDRS Part III score (on state). Data were obtained from seven RCTs, including 2205 patients. Compared to placebo on primary and secondary outcome, istradefylline group both showed significant reductions (WMD -0.60, p = 0.0001; WMD -1.07, p = 0.002). Subgroup analysis suggested that istradefylline 20, 40, and 60 mg/day in both group showed significant reductions on the two outcomes. Based on these results, Istradefylline could be an efficacy and safety augmentation drug added on to levodopa or other existing anti-Parkinsonian therapies. Limited by the number of studies, future large-scale studies are needed to verify these results, assess the long-term effect of istradefylline and the effect of istradefylline as monotherapy, and find the most effective dose of istradefylline.

The Adenosine A2A-Receptor Antagonist Istradefylline Enhances the Motor Response of l-DOPA Without Worsening Dyskinesia in MPTP-Treated Common Marmosets

The adenosine A2A-receptor antagonist istradefylline decreases OFF time in patients with Parkinson’s disease who are already treated with optimal doses of dopaminergic medication but can cause an increase in non-troublesome dyskinesia. Preclinical experiments have shown that A2A antagonists are most effective in potentiating motor function when combined with submaximal doses of l-DOPA. However, the effects of combining istradefylline with sub-optimal l-DOPA treatment on established dyskinesia have not been studied. We now examine the effects of acute and repeated administration of istradefylline on dyskinesia in MPTP-treated common marmosets previously primed to exhibit involuntary movements by prior exposure to l-DOPA. In these animals, single dose acute oral administration of istradefylline (10 mg/kg) enhanced and prolonged the anti-parkinsonian effects of a sub-optimal dose of l-DOPA (2.5 mg/kg). The chronic co-administration of istradefylline (10 mg/kg) with l-DOPA (2.5 mg/kg) for 21 days did not worsen the severity of existing dyskinesia. Rather, the severity of dyskinesia tended to be reduced over the 21-day treatment period. These results suggest that istradefylline can be used to potentiate the effects of sub-optimal doses of l-DOPA in the treatment of Parkinson’s disease without causing or worsening dyskinesia.