Search Results (22)

Stroke, the third leading cause of death worldwide, is a major cause of functional disability. Cerebral ischemia causes a rapid elevation of adenosine, the main neuromodulator in the brain. The inhibition of adenosine A2A receptors (A2ARs) has been introduced as a potential target in neurodegenerative disorders involving extracellular adenosine elevation. Istradefylline, a selective A2AR antagonist, has been approved for Parkinson’s disease (PD) adjunctive therapy and showed neuroprotective effects in PD and Alzheimer’s disease. However, the role of A2ARs in post-stroke neuronal damage and behavioral deficits remains unclear. We recently showed that A2AR antagonism prevented the adenosine-induced post-hypoxia synaptic potentiation of glutamatergic neurotransmission following the hypoxia/reperfusion of hippocampal slices. Here, we investigated the potential neuroprotective effects of istradefylline in male Sprague-Dawley rats subjected to pial vessel disruption (PVD) used to model a small-vessel stroke. Rats were treated with either a vehicle control or istradefylline (3 mg/kg i.p.) following PVD surgery for three days. Istradefylline administration prevented anxiety and depressive-like behaviors caused by PVD stroke. In addition, istradefylline significantly attenuated ischemia-induced cognitive impairment and motor deficits. Moreover, istradefylline markedly reduced hippocampal neurodegeneration, as well as GFAP/Iba-1, TNF-α, nNOS, and iNOS levels after PVD, but prevented the downregulation of anti-inflammatory markers TGF-β1 and IL-4. Together, these results suggest a molecular link between stroke and PD and that the anti-PD drug istradefylline displays translational potential for drug repurposing as a neuroprotective agent for cerebral ischemic damage. Full article

Parkinson’s disease (PD) represents a growing challenge to global health, as it involves millions of people. The high grade of disability is due to the loss of dopaminergic neuron activity, and levodopa is the gold-standard therapy used to restore dopamine in the dopamine-denervated regions. Another therapeutic approach is the use of A_2A adenosine receptor antagonists and, among them, istradefylline is the only one currently approved for therapy in association with levodopa. In this work, we synthesized A_2A adenosine receptor antagonists represented by 9-ethyl-2,8-disubstituted adenine derivatives, which were tested at human adenosine receptors in binding and functional assays. These compounds showed A_2A adenosine receptor-binding affinities in the low nanomolar range and 1, 4, and 5 exhibited good potency in the functional assays. Hence, they were evaluated in in vivo rat models of PD, where they were demonstrated to revert haloperidol-induced catalepsy and potentiate levodopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats. The most potent derivative, 4, was then evaluated in the tacrine model, where it reduced the tremulous jaw movements, therefore demonstrating an action on parkinsonian tremor. These data revealed 8-ethoxy-2-phenethoxy-9-ethyladenine (4) as an A_2A adenosine receptor antagonist endowed with antiparkinsonian effects and as a good candidate to treat the disease. Full article

Glioblastoma (GBM) is a highly lethal type of cancer, frequently presenting an unfavorable prognosis. The current treatment options for this neoplasia are still limited, highlighting the need for further research evaluating new drugs to treat GBM or to serve as an adjuvant to improve the efficiency of currently used therapies. In this sense, the inhibition of A2A receptors in the brain has presented a neuroprotective role for several diseases, such as neurodegenerative conditions, and it has been suggested as a possible pharmacological target in some types of cancer; thus, it also can be underscored as a potential target in GBM. Recently, Istradefylline (IST) was approved by the FDA for treating Parkinson’s disease, representing a safe drug that acts through the inhibition of the A2A receptor, and it has also been suggested as an antineoplastic drug. Therefore, this work aims to explore the effects of A2A receptor inhibition as a therapy for GBM and assess the feasibility of this blockage occurring through the effects of IST. Full article

Mitochondrial dysfunction is well-established in Parkinson’s disease (PD); however, its dysfunctions associating with cell organelle connectivity remain unknown. We aimed to establish the crucial cytosolic protein involved in organelle connectivity between mitochondria and the endopalmic reticulum (ER) through a computational approach by constructing an organelle protein network to extract functional clusters presenting the crucial PD protein connecting organelles. Then, we assessed the influence of anti-parkinsonism drugs (n = 35) on the crucial protein through molecular docking and molecular dynamic simulation and further validated its gene expression in PD participants under, istradefylline (n = 25) and amantadine (n = 25) treatment. Based on our investigation, D-aspartate oxidase (DDO )protein was found to be the critical that connects both mitochondria and the ER. Further, molecular docking showed that istradefylline has a high affinity (−9.073 kcal/mol) against DDO protein, which may disrupt mitochondrial-ER connectivity. While amantadine (−4.53 kcal/mol) shows negligible effects against DDO that contribute to conformational changes in drug binding, Successively, DDO gene expression was downregulated in istradefylline-treated PD participants, which elucidated the likelihood of an istradefylline off-target mechanism. Overall, our findings illuminate the off-target effects of anti-parkinsonism medications on DDO protein, enabling the recommendation of off-target-free PD treatments. Full article

Cognitive impairment in patients with Parkinson’s disease (PD) is one of the commonest and most disabling non-motor manifestations during the course of the disease. The clinical spectrum of PD-related cognitive impairment includes subjective cognitive decline (SCD), mild cognitive impairment (MCI) and PD dementia (PDD). As the disease progresses, cognitive decline creates a significant burden for the family members and/or caregivers of patients with PD, and has a great impact on quality of life. Current pharmacological treatments have demonstrated partial efficacy and failed to halt disease progression, and novel, effective, and safe therapeutic strategies are required. Accumulating preclinical and clinical evidence shows that several agents may provide beneficial effects on patients with PD and cognitive impairment, including ceftriaxone, ambroxol, intranasal insulin, nilotinib, atomoxetine, mevidalen, blarcamesine, prasinezumab, SYN120, ENT-01, NYX-458, GRF6021, fosgonimeton, INT-777, Neuropeptide S, silibinin, osmotin, cordycepin, huperzine A, fibroblast growth factor 21, Poloxamer 188, ginsenoside Rb1, thioredoxin-1, tangeretin, istradefylline and Eugenia uniflora. Potential underlying mechanisms include the inhibition of a-synuclein aggregation, the improvement of mitochondrial function, the regulation of synaptic plasticity, an impact on the gut–brain axis, the modulation of neuroinflammation and the upregulation of neurotrophic factors, as well as cholinergic, dopaminergic, serotoninergic and norepinephrine neurotransmission. In this updated overview, we aim to cover the clinical aspects of the spectrum of PD-related cognitive impairment and discuss recent evidence on emerging treatment approaches that are under investigation at a preclinical and clinical level. Finally, we aim to provide additional insights and propose new ideas for investigation that may be feasible and effective for the spectrum of PD-related cognitive impairment. Full article

Dissolution limitations to oral absorption can occur if the time required for dissolution is longer than the transit time across the small intestine and/or if dissolution is slower than the drug’s permeation through the gut wall. These limitations most often occur for poorly soluble drugs. A standard method for overcoming dissolution issues is to reduce the particle size of the (solid) drug. Building on the refined Developability Classification System (rDCS), this work establishes a novel set of equations with which the appropriate degree of particle size reduction needed to mitigate dissolution limitations to absorption can be calculated. According to the type of data available, the appropriate equation(s) for each situation can be applied. Three case examples are used to illustrate implementation of the equations: voriconazole, lemborexant and istradefylline. Although for voriconazole (rDCS Class I) target radius (r_target) estimates indicate that particle size reduction is unnecessary, for lemborexant (rDCS Class I) a radius of ≤20 µm would be required to improve absorption. For istradefylline (rDCS Class IIb) the r_target was approximately 12 µm. Results are commensurate with literature information for these three drugs, signaling that the equations are suitable for application to a wide variety of drug substances. Full article

De novo mutations affecting the G protein α o subunit (Gαo)-encoding gene (GNAO1) cause childhood-onset developmental delay, hyperkinetic movement disorders, and epilepsy. Recently, we established Caenorhabditis elegans as an informative experimental model for deciphering pathogenic mechanisms associated with GNAO1 defects and identifying new therapies. In this study, we generated two additional gene-edited strains that harbor pathogenic variants which affect residues Glu²⁴⁶ and Arg²⁰⁹—two mutational hotspots in Gαo. In line with previous findings, biallelic changes displayed a variable hypomorphic effect on Gαo-mediated signaling that led to the excessive release of neurotransmitters by different classes of neurons, which, in turn, caused hyperactive egg laying and locomotion. Of note, heterozygous variants showed a cell-specific dominant-negative behavior, which was strictly dependent on the affected residue. As with previously generated mutants (S47G and A221D), caffeine was effective in attenuating the hyperkinetic behavior of R209H and E246K animals, indicating that its efficacy is mutation-independent. Conversely, istradefylline, a selective adenosine A_2A receptor antagonist, was effective in R209H animals but not in E246K worms, suggesting that caffeine acts through both adenosine receptor-dependent and receptor-independent mechanisms. Overall, our findings provide new insights into disease mechanisms and further support the potential efficacy of caffeine in controlling dyskinesia associated with pathogenic GNAO1 mutations. Full article

Cardiac fibrosis is a common pathological feature of different cardiovascular diseases, characterized by the aberrant deposition of extracellular matrix (ECM) proteins in the cardiac interstitium, myofibroblast differentiation and increased fibrillar collagen deposition stimulated by transforming growth factor (TGF)-β activation. Biglycan (BGN), a small leucine-rich proteoglycan (SLRPG) integrated within the ECM, plays a key role in matrix assembly and the phenotypic control of cardiac fibroblasts. Moreover, BGN is critically involved in pathological cardiac remodeling through TGF-β binding, thus causing myofibroblast differentiation and proliferation. Adenosine receptors (ARs), and in particular A_2AR, may play a key role in stimulating fibrotic damage through collagen production/deposition, as a consequence of cyclic AMP (cAMP) and AKT activation. For this reason, A_2AR modulation could be a useful tool to manage cardiac fibrosis in order to reduce fibrotic scar deposition in heart tissue. Therefore, the aim of the present study was to investigate the possible crosstalk between A_2AR and BGN modulation in an in vitro model of TGF-β-induced fibrosis. Immortalized human cardiac fibroblasts (IM-HCF) were stimulated with TGF-β at the concentration of 10 ng/mL for 24 h to induce a fibrotic phenotype. After applying the TGF-β stimulus, cells were treated with two different A_2AR antagonists, Istradefylline and ZM241385, for an additional 24 h, at the concentration of 10 µM and 1 µM, respectively. Both A_2AR antagonists were able to regulate the oxidative stress induced by TGF-β through intracellular reactive oxygen species (ROS) reduction in IM-HCFs. Moreover, collagen1a1, MMPs 3/9, BGN, caspase-1 and IL-1β gene expression was markedly decreased following A_2AR antagonist treatment in TGF-β-challenged human fibroblasts. The results obtained for collagen1a1, SMAD3, α-SMA and BGN were also confirmed when protein expression was evaluated; phospho-Akt protein levels were also reduced following Istradefylline and ZM241385 use, thus suggesting that collagen production involves AKT recruited by the A_2AR. These results suggest that A_2AR modulation might be an effective therapeutic option to reduce the fibrotic processes involved in heart pathological remodeling. Full article

Istradefylline as a selective adenosine A_2A-receptor antagonist is clinically used to treat Parkinson’s disease and improve dyskinesia in its early stages. However, its crystal form, as an important factor in the efficacy of the drug, is rarely studied. Herein, three kinds of crystal forms of istradefylline prepared from ethanol (form I), methanol (form II), and acetonitrile (form III) are reported by use of a crystal engineering strategy. These three crystal forms were characterized and made into tablets for dissolution testing. Both the solubility and the dissolution rates were also determined. The dissolution rate of form I and form III is significantly higher than form II at pH 1.2 (87.1%, 58.2%, and 87.7% for form I, form II, and form III, respectively), pH 4.5 (88.1%, 58.9%, and 87.1% for form I, form II, and form III, respectively) and pH 6.8 (87.5%, 58.2%, and 86.0% for form I, form II, and form III, respectively) at 60 min. Considering the prepared solution and the proper dissolution profile, form I is anticipated to possess promising absorption for bioavailability. Full article

The main goal of this study was to determine the antidepressant-like potential of the co-administration of sodium selenite (Se) and the selective adenosine A1 and A2A antagonists DPCPX and istradefylline (IST), respectively, in mice despair tests. Biochemical studies were performed to elucidate the action mechanisms of the investigated treatment strategies. The results confirmed that, when administered by itself, Se exerts an antidepressant-like effect in the FST and TST and that this activity is dose-dependent. Further experiments demonstrated that Se (0.25 mg/kg) significantly enhanced the activity of mice in both tests when co-administered with DPCPX (1 mg/kg) and IST (0.5 mg/kg) at doses which would be ineffective if administered individually. Our research revealed that neither DPCPX, IST, nor Se or combinations of the tested substances induced significant changes in the brain-derived neurotrophic factor (BDNF) levels in mice serum vs. the NaCl-treated group. However, we observed a decrease in the mRNA level of antioxidant defense enzymes. Molecular studies also showed changes in the expression of the Slc6a15, Comt, and Adora1 genes, particularly after exposure to the combination of Se and DPCPX, which indicates a beneficial effect and may help to explain the key mechanism of the antidepressant effect. The combination of Se with substances attenuating adenosine neurotransmission may become a new therapeutic strategy for patients with depression. Full article

The cerebral expression of the A_2A adenosine receptor (A_2AAR) is altered in neurodegenerative diseases such as Parkinson’s (PD) and Huntington’s (HD) diseases, making these receptors an attractive diagnostic and therapeutic target. We aimed to further investigate the pharmacokinetic properties in the brain of our recently developed A_2AAR–specific antagonist radiotracer [¹⁸F]FLUDA. For this purpose, we retrospectively analysed dynamic PET studies of healthy mice and rotenone–treated mice, and conducted dynamic PET studies with healthy pigs. We performed analysis of mouse brain time–activity curves to calculate the mean residence time (MRT) by non–compartmental analysis, and the binding potential (BP_ND) of [¹⁸F]FLUDA using the simplified reference tissue model (SRTM). For the pig studies, we performed a Logan graphical analysis to calculate the radiotracer distribution volume (V_T) at baseline and under blocking conditions with tozadenant. The MRT of [¹⁸F]FLUDA in the striatum of mice was decreased by 30% after treatment with the A_2AAR antagonist istradefylline. Mouse results showed the highest BP_ND (3.9 to 5.9) in the striatum. SRTM analysis showed a 20% lower A_2AAR availability in the rotenone–treated mice compared to the control–aged group. Tozadenant treatment significantly decreased the V_T (14.6 vs. 8.5 mL · g⁻¹) and BP_ND values (1.3 vs. 0.3) in pig striatum. This study confirms the target specificity and a high BP_ND of [¹⁸F]FLUDA in the striatum. We conclude that [¹⁸F]FLUDA is a suitable tool for the non–invasive quantitation of altered A_2AAR expression in neurodegenerative diseases such as PD and HD, by PET. Full article

The A_2A adenosine receptor is a protein belonging to a family of four GPCR adenosine receptors. It is involved in the regulation of several pathophysiological conditions in both the central nervous system and periphery. In the brain, its localization at pre- and postsynaptic level in striatum, cortex, hippocampus and its effects on glutamate release, microglia and astrocyte activation account for a crucial role in neurodegenerative diseases, including Alzheimer’s disease (AD). This ailment is considered the main form of dementia and is expected to exponentially increase in coming years. The pathological tracts of AD include amyloid peptide-β extracellular accumulation and tau hyperphosphorylation, causing neuronal cell death, cognitive deficit, and memory loss. Interestingly, in vitro and in vivo studies have demonstrated that A_2A adenosine receptor antagonists may counteract each of these clinical signs, representing an important new strategy to fight a disease for which unfortunately only symptomatic drugs are available. This review offers a brief overview of the biological effects mediated by A_2A adenosine receptors in AD animal and human studies and reports the state of the art of A_2A adenosine receptor antagonists currently in clinical trials. As an original approach, it focuses on the crucial role of pharmacokinetics and ability to pass the blood–brain barrier in the discovery of new agents for treating CNS disorders. Considering that A_2A receptor antagonist istradefylline is already commercially available for Parkinson’s disease treatment, if the proof of concept of these ligands in AD is confirmed and reinforced, it will be easier to offer a new hope for AD patients. Full article

The adenosine A_2A receptor subtype is recognized as a non-dopaminergic pharmacological target for the treatment of neurodegenerative disorders, notably Parkinson’s disease (PD). The selective A_2A receptor antagonist istradefylline is approved in the US and Japan as an adjunctive treatment to levodopa/decarboxylase inhibitors in adults with PD experiencing OFF episodes or a wearing-off phenomenon; however, the full potential of this drug class remains to be explored. In this article, we review the pharmacology of adenosine A_2A receptor antagonists from the perspective of the treatment of both motor and non-motor symptoms of PD and their potential for disease modification. Full article

A_2A adenosine receptors (A_2A-AR) have a cardio-protective function upon ischemia and reperfusion, but on the other hand, their stimulation could lead to arrhythmias. Our aim was to investigate the potential use of the PET radiotracer [¹⁸F]FLUDA to non-invasively determine the A_2A-AR availability for diagnosis of the A_2AR status. Therefore, we compared mice with cardiomyocyte-specific overexpression of the human A_2A-AR (A_2A-AR TG) with the respective wild type (WT). We determined: (1) the functional impact of the selective A_2AR ligand FLUDA on the contractile function of atrial mouse samples, (2) the binding parameters (B_{max and} K_D) of [¹⁸F]FLUDA on mouse and human atrial tissue samples by autoradiographic studies, and (3) investigated the in vivo uptake of the radiotracer by dynamic PET imaging in A_2A-AR TG and WT. After A_2A-AR stimulation by the A_2A-AR agonist CGS 21680 in isolated atrial preparations, antagonistic effects of FLUDA were found in A_2A-AR-TG animals but not in WT. Radiolabelled [¹⁸F]FLUDA exhibited a K_D of 5.9 ± 1.6 nM and a B_max of 455 ± 78 fmol/mg protein in cardiac samples of A_2A-AR TG, whereas in WT, as well as in human atrial preparations, only low specific binding was found. Dynamic PET studies revealed a significantly higher initial uptake of [¹⁸F]FLUDA into the myocardium of A_2A-AR TG compared to WT. The hA_2A-AR-specific binding of [¹⁸F]FLUDA in vivo was verified by pre-administration of the highly affine A_2AAR-specific antagonist istradefylline. Conclusion: [¹⁸F]FLUDA is a promising PET probe for the non-invasive assessment of the A_2A-AR as a marker for pathologies linked to an increased A_2A-AR density in the heart, as shown in patients with heart failure. Full article

Parkinson’s Disease (PD) is a disease that involves neurodegeneration and is characterised by the motor symptoms which include muscle rigidity, tremor, and bradykinesia. Other non-motor symptoms include pain, depression, anxiety, and psychosis. This disease affects up to ten million people worldwide. The pathophysiology behind PD is due to the neurodegeneration of the nigrostriatal pathway. There are many conventional drugs used in the treatment of PD. However, there are limitations associated with conventional drugs. For instance, levodopa is associated with the on-off phenomenon, and it may induce wearing off as time progresses. Therefore, this review aimed to analyze the newly approved drugs by the United States-Food and Drug Administration (US-FDA) from 2016–2019 as the adjuvant therapy for the treatment of PD symptoms in terms of efficacy and safety. The new drugs include safinamide, istradefylline and pimavanserin. From this review, safinamide is considered to be more efficacious and safer as the adjunct therapy to levodopa as compared to istradefylline in controlling the motor symptoms. In Study 016, both safinamide 50 mg (p = 0.0138) and 100 mg (p = 0.0006) have improved the Unified Parkinson’s Disease Rating Scale (UPDRS) part III score as compared to placebo. Improvement in Clinical Global Impression—Change (CGI-C), Clinical Global Impression—Severity of Illness (CGI-S) and off time were also seen in both groups of patients following the morning levodopa dose. Pimavanserin also showed favorable effects in ameliorating the symptoms of Parkinson’s Disease Psychosis (PDP). A combination of conventional therapy and non-pharmacological treatment is warranted to enhance the well-being of PD patients. Full article