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Pharmacology and Therapeutic Activity of Purinergic Drugs for Disorders of the ... When we discuss purinergic signalling and purinergic mechanisms, it is worth ...
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CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 6

649

Editorial Pharmacology and Therapeutic Activity of Purinergic Drugs for Disorders of the Nervous System When we discuss purinergic signalling and purinergic mechanisms, it is worth remembering that after the initial formulation of the purinergic theory back in the early 1970s, suggesting the role of nucleotides as neurotransmitters or co-transmitters, and nucleosides as neuromodulators in the nervous system, this novel idea encountered considerable resistance over the next 20 years. Overcoming the reticence that has always characterized the purinergic question in the past, the most modern frontiers in neurobiology are at last beginning to fully appreciate this field, and the purinergic issue is definitely accepted now, with a burst of interest in many distinct directions, including the exploitation of purinergic receptors, transporters and nucleotidases as druggable targets against a large number of neuropathological conditions. Over the years, the progressively more sophisticated techniques and multifaceted experimental designs that have been developed and sustained by state-of-the-art computer software, have also allowed the scrutiny of the intricacy of purinergic interactions down to the molecular level. Theoretical investigations, computational analysis, and molecular modelling are now further facilitating the development of novel and potent purinergic therapeutic agents that can soon enter into the different phases of clinical trials. In general, what we have discovered up till now about the contribution of purinergic mechanisms in, for instance, the insurgence and progression of neurodegenerative and neuroinflammatory conditions in the nervous system, is that a large-scale interaction of purinergic receptors with ectoenzymes and purinergic transporters occurring at the plasma membrane, drives the overall response of neurons and glial cells to purine and pyrimidine ligands. There is not a single interaction that becomes privileged over another, but only a choral, space-time coincident event can explain the multipurpose and multidirectional nature of the information delivered by extracellular purinergic and pyrimidinergic molecules. The rationale of the present Hot Topic Issue on the “Pharmacology and therapeutic activity of purinergic drugs for disorders of the nervous system” is to highlight some pharmacological, molecular and functional features of purinergic receptors for nucleosides and nucleotides, along with both the enzymes responsible for their mutual conversion, and the proteins devoted to their in and out transport at the plasma membrane. In particular, we aim to illustrate their involvement in the insurgence and progression of neurodegenerative and neuroinflammatory conditions in the nervous system (Table 1). What we note at a glance from the results shown in this comprehensive issue is that there is still a limited amount of information that characterizes some of the components of the purinergic machinery, to the point that selected purinergic receptors, ectonucleotidases or transporters have regrettably to be considered as “neglected”, when referred to the physiology or even more to the pathology of the nervous system. This is the case, for instance, of the ionotropic P2X5R and P2X6R subtypes, in particular in Alzheimer’s disease, amyotrophic lateral sclerosis, epilepsy, Huntington’s disease, ischemia, mood disorders, multiple sclerosis, neuropathic pain and Parkinson’s disease, while P2X3R and P2X4R are apparently involved only in pain conditions. The same is confirmed also for the metabotropic P2Y4R, P2Y6R, P2Y11R, P2Y13R and P2Y14R subtypes still having an unexplored role in these same pathological conditions, while A1 and A3 subtypes are apparently involved largely in ischemic conditions (Table 1). Table 1.

Purinergic Targets in Nervous System Diseases

Purinergic Players P2X receptors X1 X2 X3 X4 X5 X6 X7 P2Y receptors Y1 Y2 Y4 Y6 Y11 Y12 Y13 Y14 Adenosine receptors A1 A2A A2B A3 Enzymes/Transporters ENPP TNAP CD39 CD73 ENT1

AD

ALS

Epilepsy

HD

Ischemia

Mood Disorders

MS

Pain

PD

(7)

(7)

(7)

(7)

(4) (4) (7)

(7)

(7)

(4) (5) (6) (7)

(7)

(8) (8) -

-

-

-

(8) -

(8) -

(10) -

(8) (10) (10) -

-

(3) -

(3) -

(3) -

(3) -

(2) (3) (2)

(3) -

-

(3) -

(3) (3) -

(9) (9) -

-

(9) (9) -

(9)

(9)

(9)

-

-

(9) (9) -

-

650

CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 6

Editorial

Evidence is presented about the involvement of P2X, P2Y and P1 receptor subtypes and purinergic enzymes/transporters in major pathological conditions of the nervous system, as described in the different chapters of this issue (numbers in parentheses refer to specific chapters). Moreover, with this Hot Topic Issue we wish to present the evidence for those purinergic ligands and/or modulators that are already, or may soon enter into clinical trials in the context of nervous system disorders. A number of purinergic receptor subtypes, ectonucleotidases and transporters have been known for a long time to be involved in several diverse neuropathological conditions, and various P1 and P2 receptor ligands are in preclinical studies and clinical trials for peripheral pathologies and diseases (Table 2). Among these compounds, we mention the highly successful use of clopidogrel, a P2Y12R antagonist for stroke, and the major efforts being made by several pharmaceutical companies to develop P2X receptor antagonists for use in clinical trials against visceral and neuropathic pain. However, only a few compounds targeting these purinergic proteins are currently used in clinical trials for the nervous system (Table 2). Among these, we mention P1 receptor antagonists, such as preladenant and istradefylline (KW-6002), for use in Parkinson's disease. In addition, the broad range adenosine antagonist, caffeine, acting locally on basal ganglia circuits and substantia nigra, is under scrutiny for use against Parkinson's disease, supported by numerous epidemiological studies linking caffeine to an improvement of motor control and levodopa serum concentrations. Table 2.

Clinical Trials with P1 and P2 Receptors Ligands Receptor

Compound

Action

P1

Adenosine

Agonist

P1

Theophylline

Antagonist

P1

Caffeine

Antagonist

A1 A1 A1 A2A A2A

Agonist Agonist Antagonist Agonist Antagonist

A2A

GW493838 INO-8875 Rolofylline BVT.115959 Istradefylline (KW-6002) [123I]MNI-420

A2A A2A

Preladenant SYN115

Antagonist Antagonist

A2A A2A

Aminophylline Regadenoson

Antagonist Agonist

A3

CF 101

Agonist

A3 P2X3 P2X7 P2X7 P2X7 P2Y12

CF 102 AF-219 AZD9056 CE-224,535 GSK1482160 Prasugrel Clopidogrel Cangrelor PRT060128 AZD6140 Clopidogrel Prasugrel

Agonist Antagonist Antagonist Antagonist Antagonist Antagonist

P2Y12 P2Y12

Antagonist

Antagonist Antagonist

Data are collected from www.clinicaltrial.gov and are updated till July 2012.

Condition Perioperative Pain Cardiovascular diseases Cerebral Ischemia Chronic Obstructive Pulmonary Disease Leukemia Chronic pain Cognitive Function, Mood Excessive Daytime Somnolence Ischemia-Reperfusion Injury Parkinson's Disease Pain/migraine disorders Apnea of Prematurity Endotoxemia Neuropathic Pain Glaucoma Heart Failure Neuropathic Pain Parkinson's Disease Restless Legs Syndrome Hungtinton’s Disease Parkinson's Disease Parkinson's Disease Parkinson's Disease Cocaine Dependence Venoarteriolar Reflex Cardiovascular diseases Sickle Cell Disease Rheumatoid Arthritis Plaque Psoriasis Chronic Hepatitis C Chronic Cough Rheumatoid Arthritis Rheumatoid Arthritis Inflammatory pain Cardiovascular diseases

Brain Infarction Chronic Asthma Sickle Cell Disease

Editorial

CNS & Neurological Disorders - Drug Targets, 2012, Vol. 11, No. 6

651

Overall, in this Hot Topic Special Issue we provide a compilation of articles about the pharmacology and therapeutic potential of the purinergic players recruited during the onset and/or progression of some major diseases of the nervous system. Notwithstanding the overabundance of information gathered so far, we wish to stimulate a scientific debate on “what is still missing” in our knowledge of the purinergic complexity, and on “what is needed next”, in order to finally extend the flow of information to all the different components of the purinergic machinery, and to translate the purinergic compounds into effective cures or preventions against nervous system pathologies. By considering the ubiquitous expression of all the purinergic players in many different cell types, tissues, organs and organisms, we estimate that the future of purinergic therapeutic developments might still be unpredictable, but, without doubt, promising.

G. Burnstock

C. Volonté

(Guest Editor) Autonomic Neuroscience Centre University College Medical School London UK E-mail: [email protected]

(Guest Editor) CNR-IBCN/S. Lucia Foundation Via Del Fosso di Fiorano 65 00143 Rome Italy E-mail: [email protected]

PMID: 22963433