Ticagrelor: a cardiometabolic drug targeting erythrocyte-mediated purinergic signaling?

Cardiometabolic diseases lead to vascular complications, which cause increasing morbidity and mortality worldwide. The underlying mechanisms are multifactorial and complex but may involve altered purinergic signaling that significantly contributes to cardiovascular dysfunction. Ticagrelor is a successful purinergic drug directly targeting ADP-mediated P2Y12R signaling for platelet aggregation and is widely used in patients with acute coronary syndrome. In addition, ticagrelor can target red blood cells (RBCs) to release ATP and inhibit adenosine uptake by RBCs, which subsequently activate purinergic signaling. This involvement in purinergic signaling may allow ticagrelor to mediate pleiotropic effects and contribute to the beneficial cardiovascular outcomes observed in clinical studies. Recent studies have established a novel function of RBCs, which is that RBCs act as disease mediators for the development of cardiovascular complications in type 2 diabetes (T2D). RBC-released ATP is defective in T2D, which has implications for the induction of vascular dysfunction by dysregulating purinergic signaling. Ticagrelor might target RBCs and restore the bioavailability of ATP and adenosine, thereby attenuating cardiovascular complications. The present perspective discusses the pleiotropic effect of ticagrelor, with a focus on the possibility of ticagrelor for the treatment of cardiometabolic complications by targeting RBCs and initiating purinergic activation. A better understanding of the proposed cardiometabolic effects could support novel clinical indications for ticagrelor application.

The Therapeutic Potential of Purinergic Receptors in Alzheimer's Disease and Promising Therapeutic Modulators.

Recent studies have proven that the purinergic signaling pathway plays a key role in neurotransmission and neuromodulation, and is involved in various neurodegenerative diseases and psychiatric disorders. With the characterization of the subtypes of receptors in purinergic signaling, i.e. the P1 (adenosine), P2X (ion channel) and P2Y (G protein-coupled), more attention has been paid to the pathophysiology and therapeutic potential of purinergic signaling in the central nervous system disorders. Alzheimer's disease (AD) is a progressive and deadly neurodegenerative disease that is characterized by memory loss, cognitive impairment and dementia. However, as drug development aimed to prevent or control AD has series of failures in recent years, more researchers have focused on the neuroprotection-related mechanisms such as purinergic signaling in AD patients to find a potential cure. This article reviews the recent discoveries of purinergic signaling in AD, and summarizes the potential agents as modulators for the receptors of purinergic signaling in AD-related research and treatments. Thus, our paper provides an insight into purinergic signaling in the development of anti- AD therapies.

More purinergic receptors deserve attention as therapeutic targets for the treatment of cardiovascular disease.

Cardiovascular disease is a major cause of morbidity and mortality worldwide. Innovative new treatment options for this cardiovascular pandemic are urgently needed. Activation of purinergic receptors (PRs) is critically involved in the development and progression of cardiovascular disease including atherosclerosis, ischemic heart disease, hypertension, and diabetes. PRs have been targeted for the treatment of several cardiovascular diseases in a clinical setting. The P2Y12R antagonists such as clopidogrel, ticagrelor, and others are the most successful class of purinergic drugs targeting platelets for the treatment of acute coronary syndrome. In addition to targeting platelets, ticagrelor may exert P2Y12R-independent effect by targeting erythrocyte-mediated purinergic activation. The partial A1R agonist neladenoson and the A2AR agonist regadenoson have been applied in cardiovascular medicine. In experimental studies, many other PRs have been shown to play a significant role in the development and progression of cardiovascular diseases, and targeting these receptors have resulted in promising outcomes. Therefore, many of these PRs including A2BR, A3R, P2X3R, P2X4R, P2X7R, P2Y1R, P2Y4R, P2Y6R, and P2Y11R can be considered as therapeutic targets. However, the multitude of PR subtypes expressed in different cells of the cardiovascular system may constitute a challenge whether single or multiple receptors should be targeted at the same time for the best efficacy. The present review discusses the promising purinergic drugs used in clinical studies for the treatment of cardiovascular disease. We also update experimental evidence for many other PRs that can be considered as therapeutic targets for future drug development.

Tackling Chronic Pain and Inflammation through the Purinergic System.

The purinergic system is composed of purine and pyrimidine transmitters, the enzymes that modulate the interconversion of nucleotides and nucleosides, the membrane transporters that control their extracellular concentrations, and the many receptor subtypes that are responsible for their cellular responses. The components of this system are ubiquitously localized in all tissues and organs, and their involvement in several physiological conditions has been clearly demonstrated. Moreover, extracellular purine and pyrimidine concentrations rise several folds under pathological conditions like tissue damage, ischemia, and inflammation, which suggest that this signaling system might contribute both to disease outcome and, possibly, to its tentative resolution. The complexity of this system has greatly impaired the clear identification of the mediators and receptors that are actually involved in a given pathology, also due to the often opposite roles played by the various receptor subtypes. Nevertheless, this knowledge is fundamental for the possible exploitation of these molecular entities as targets for the development of new pharmacological approaches. In this review, we aim at highlighting what is currently known on the role of the purinergic system in various pain conditions and during inflammatory processes. Although some confusion may arise from conflicting results, literature data clearly show that targeting specific purinergic receptors may represent an innovative approach to various pain and inflammatory conditions, and that new purine-based drugs are now very close to reach the market with these indications.

Introduction to the Special Issue on Purinergic Receptors.

In this Introduction to the series of papers that follow about purinergic receptors, there is a brief history of the discovery of purinergic signalling, the identity of purinoceptors and the current recognition of P1, P2X and P2Y subtypes. An account of key functions mediated by purinoceptors follows, including examples of both short-term and long-term (trophic) signalling and a table showing the selective agonists and antagonists for the purinoceptor subtypes. References to evolution and roles of purinoceptors in pathological conditions are also presented.

Motor complications in Parkinson's disease: a comprehensive review of emergent management strategies.

Motor complications (dyskinesias and motor fluctuations) are a common and disabling problem of dopaminergic therapy in Parkinson's disease, which are often difficult to treat with the current therapeutic strategies. It has been proposed that continuous dopaminergic delivery could reduce the emergence of motor complications, which has been tried with levodopa intestinal infusion or subcutaneous apomorphine infusion. In selected refractory cases, surgical approaches such as deep brain stimulation should be considered. Ongoing clinical and preclinical research tried to lead the field into the discovery of other therapeutic targets and strategies that might prevent or reduce motor complications. These include drugs targeting non-dopaminergic systems (e.g. glutamatergic, serotonergic, noradrenergic, adenosinergic and cholinergic systems), gene therapy for delivering neurotrophic factors or critical enzymes for dopamine synthesis, and cell therapy. These studies found variable results, some of them promising, with the possibility of new therapeutic armamentarium in the management of Parkinson's disease in the near future.

ENaC inhibitors and airway re-hydration in cystic fibrosis: state of the art.

Cystic fibrosis (CF) is a hereditary disease caused by mutations in the gene encoding the chloride channel "cystic fibrosis transmembrane conductance regulator" (CFTR). The lack of functional CFTR in CF airways leads to impaired ion and fluid homeostasis of the fluid layer which lines the airway surfaces (ASL). The ASL is important for proper ciliary beat and clearance of mucus from the airways. According to the "low volume hypothesis", CF airway epithelia hyperabsorb sodium via the epithelial sodium channel (ENaC). Although the contribution of ENaC to CF pathogenesis is still under debate, there is convincing data demonstrating that re-hydration of the ASL might improve mucociliary clearance in CF patients. ASL re-hydration might, amongst other things, be achieved by a block of airway transepithelial sodium absorption with inhibitors of ENaC. This mini-review article describes the role of ENaC in ASL fluid homeostasis and rehydration, and summarizes the current state of the art in the discovery and establishment of compounds which inhibit ENaC activity and may represent pharmacological tools for the treatment of CF.

Therapeutic applications.

The current treatments offered to patients with chronic respiratory diseases are being re-evaluated based on the loss of potency during long-term treatments or because they only provide significant clinical benefits to a subset of the patient population. For instance, glucocorticoids are considered the most effective anti-inflammatory therapies for chronic inflammatory and immune diseases, such as asthma. But they are relatively ineffective in asthmatic smokers, and patients with chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF). As such, the pharmaceutical industry is exploring new therapeutic approaches to address all major respiratory diseases. The previous chapters demonstrated the widespread influence of purinergic signaling on all pulmonary functions and defense mechanisms. In Chap. 8, we described animal studies which highlighted the critical role of aberrant purinergic activities in the development and maintenance of chronic airway diseases. This last chapter covers all clinical and pharmaceutical applications currently developed based on purinergic receptor agonists and antagonists. We use the information acquired in the previous chapters on purinergic signaling and lung functions to scrutinize the preclinical and clinical data, and to realign the efforts of the pharmaceutical industry.

The role of adenosine receptors in rheumatoid arthritis.

Rheumatoid arthritis (RA), is the most common inflammatory musculoskeletal disease inducing diminished quality-of-life in the affected individuals and having major impact on society due to decrease work ability. Early diagnosis and immediate, effective therapy are crucial in order to prevent unfavorable outcome. Treatment of RA has progressed during the past two decades thanks to the advent of a large number of new agents targeting different specific molecules and pathways involved in the modulation of the inflammation. In this scenario an important role is covered by adenosine, a purine nucleoside released from a variety of cells in response to metabolic and inflammatory stress, which is considered to be a potent endogenous regulator acting through its interaction with 4 cell surface receptors named as A(1), A(2A), A(2B) and A(3). Adenosine receptor stimulation has complex effects on the release of pro-inflammatory cytokines depending on selective receptor engagement. Recent data show the involvement of adenosine pathways in RA and its potential therapeutic implications.

[Purine analgesia: experimental results and clinical perspectives].

The high rate of dissatisfaction with analgesia in patients undergoing surgery and by those with chronic pain prompts a search for new pain relief methods. Purine analgesia may considerably ease suffering in these patient groups. This review considers the results of the studies dealing with the analgesic activity of non-selective purine receptor agonists, such as adenosine and adenosine triphosphate, on experimental models and the feasibilities of their clinical application. The paper points to the experimental studies, the results of which are the basis for the clinical use of purines. Much attention is given to the studies using purine analgesia as a component of general anesthesia. It is no less than important that good results of treatment were obtained after administration of purine agonists to patients with neuropathic pain syndromes. Thus, purine analgesia should be regarded as a promising line of the development of anesthesiology.