adenosine-kinase and Schizophrenia

Pharmacotherapy of schizophrenia based on the dopamine hypothesis remains unsatisfactory for the negative and cognitive symptoms of the disease. Enhancing N-methyl-D-aspartate receptors (NMDAR) function is expected to alleviate such persistent symptoms, but successful development of novel clinically effective compounds remains challenging. Adenosine is a homeostatic bioenergetic network modulator that is able to affect complex networks synergistically at different levels (receptor-dependent pathways, biochemistry, bioenergetics, and epigenetics). By affecting brain dopamine and glutamate activities, it represents a promising candidate for reversing the functional imbalance in these neurotransmitter systems believed to underlie the genesis of schizophrenia symptoms, as well as restoring homeostasis of bioenergetics. Suggestion of an adenosine hypothesis of schizophrenia further posits that adenosinergic dysfunction might contribute to the emergence of multiple neurotransmitter dysfunctions characteristic of schizophrenia via diverse mechanisms. Given the importance of adenosine in early brain development and regulation of brain immune response, it also bears direct relevance to the aetiology of schizophrenia. Here, we provide an overview of the rationale and evidence in support of the therapeutic potential of multiple adenosinergic targets, including the high-affinity adenosine receptors (A(1)R and A(2A)R), and the regulatory enzyme adenosine kinase (ADK). Key preliminary clinical data and preclinical findings are reviewed.

Topics: Adenosine; Adenosine Kinase; Animals; Antipsychotic Agents; Humans; Receptors, Purinergic P1; Schizophrenia

Nucleoside receptors are known to be important targets for a variety of brain diseases. However, the therapeutic modulation of their endogenous agonists by inhibitors of nucleoside metabolism represents an alternative therapeutic strategy that has gained increasing attention in recent years. Deficiency in endogenous nucleosides, in particular of adenosine, may causally be linked to a variety of neurological diseases and neuropsychiatric conditions ranging from epilepsy and chronic pain to schizophrenia. Consequently, augmentation of nucleoside function by inhibiting their metabolism appears to be a rational therapeutic strategy with distinct advantages: (i) in contrast to specific receptor modulation, the increase (or decrease) of the amount of a nucleoside will affect several signal transduction pathways simultaneously and therefore have the unique potential to modify complex neurochemical networks; (ii) by acting on the network level, inhibitors of nucleoside metabolism are highly suited to fine-tune, restore, or amplify physiological functions of nucleosides; (iii) therefore inhibitors of nucleoside metabolism have promise for the "soft and smart" therapy of neurological diseases with the added advantage of reduced systemic side effects. This review will first highlight the role of nucleoside function and dysfunction in physiological and pathophysiological situations with a particular emphasis on the anticonvulsant, neuroprotective, and antinociceptive roles of adenosine. The second part of this review will cover pharmacological approaches to use inhibitors of nucleoside metabolism, with a special emphasis on adenosine kinase, the key regulator of endogenous adenosine. Finally, novel gene-based therapeutic strategies to inhibit nucleoside metabolism and focal treatment approaches will be discussed.

Topics: Adenosine; Adenosine Kinase; Analgesics; Animals; Anticonvulsants; Brain; Brain Diseases; Epilepsy; Gene Expression; Humans; Metabolic Networks and Pathways; Mice; Mice, Knockout; Neuroprotective Agents; Pain; Protein Kinase Inhibitors; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Rats; Receptor, Adenosine A1; Receptor, Adenosine A2A; Schizophrenia; Signal Transduction; Sleep Wake Disorders

Adenosine is a modulator of brain function uniquely positioned to integrate excitatory and inhibitory neurotransmission. The past few years brought a wealth of new data fostering our understanding of how the adenosine system is involved in the pathogenesis of neurological diseases. Thus, dysregulation of the adenosine system is implicated in epileptogenesis and cell therapies have been developed to locally augment adenosine in an approach to prevent seizures. While activation of inhibitory adenosine A(1) receptors is beneficial in epilepsy, chronic pain and cerebral ischemia, inhibition of facilitatory A(2A) receptors has profound neuroprotective effects, which are currently exploited in clinical trials in Parkinson's disease. A new era of adenosine-based therapies has begun, with the prospect to cover a wide range of neurological diseases.

Topics: Adenosine; Adenosine Kinase; Alzheimer Disease; Animals; Brain Diseases; Brain Ischemia; Epilepsy; Humans; Huntington Disease; Pain; Parkinson Disease; Schizophrenia; Synaptic Transmission

The adenosine hypothesis of schizophrenia posits that reduced availability of the neuromodulator adenosine contributes to dysregulation of dopamine and glutamate transmission and the symptoms associated with schizophrenia. It has been proposed that increased expression of the enzyme adenosine kinase (ADK) may drive hypofunction of the adenosine system. While animal models of ADK overexpression support such a role for altered ADK, the expression of ADK in schizophrenia has yet to be examined. In this study, we assayed ADK gene and protein expression in frontocortical tissue from schizophrenia subjects. In the dorsolateral prefrontal cortex (DLPFC), ADK-long and -short splice variant expression was not significantly altered in schizophrenia compared to controls. There was also no significant difference in ADK splice variant expression in the frontal cortex of rats treated chronically with haloperidol-decanoate, in a study to identify the effect of antipsychotics on ADK gene expression. ADK protein expression was not significantly altered in the DLPFC or anterior cingulate cortex (ACC). There was no significant effect of antipsychotic medication on ADK protein expression in the DLPFC or ACC. Overall, our results suggest that increased ADK expression does not contribute to hypofunction of the adenosine system in schizophrenia and that alternative mechanisms are involved in dysregulation of this system in schizophrenia.

Topics: Adenosine; Adenosine Kinase; Adult; Aged; Aged, 80 and over; Animals; Antipsychotic Agents; Female; Gene Expression; Gyrus Cinguli; Hep G2 Cells; Humans; Male; Middle Aged; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Schizophrenia; Tissue Banks

Adenosine kinase (ADK) is supposed to be a schizophrenia susceptibility gene based on the findings that ADK is an enzyme that catalyzes transfer of the gamma-phosphate from ATP to adenosine, which interacts with dopamine and glutamate neurotransmitters. However, no reports of schizophrenia cases with loss of function variants in the ADK region have been published. In our previous study investigating copy number variants in schizophrenia, we detected a copy number variant in the ADK region in 1 of 1699 schizophrenia patients.. We validated the ADK deletion by determining the breakpoint. Then, we compared the relative expression of ADK in 32 schizophrenia patients, including a schizophrenia patient with deletion of ADK, with 29 healthy controls using lymphoblastoid cell lines. Furthermore, we evaluated the clinical phenotypes of the schizophrenia with ADK deletion.. We validated the copy number variants with Sanger sequencing and predicted that this copy number variant results in loss of function of ADK. Furthermore, expression analysis of mRNA from peripheral blood in this schizophrenia patient with the ADK deletion showed an extremely low level of ADK. Here we describe a case report of a patient with ADK deletion with phenotypes (schizophrenia, parkinsonism, epilepsy) that are predicted when ADK function is disrupted.. Considering that the patient had a low ADK mRNA level and showed a phenotype that may be related to ADK deficiency, the copy number variants in the region of ADK may be strongly related to the phenotypes described here, such as schizophrenia, Parkinsonism, and epilepsy.

Topics: Adenosine Kinase; DNA Copy Number Variations; Epilepsy; Female; Humans; Middle Aged; Parkinson Disease; Phenotype; RNA, Messenger; Schizophrenia

Prior work in animal models implicates abnormalities of adenosine metabolism in astrocytes as a possible pathophysiological mechanism underlying the symptoms of schizophrenia. In the present study, we sought to reverse-translate these findings back to the human brain in schizophrenia, focusing on the following questions: (1) Which components of the adenosine system are dysregulated in schizophrenia, and (2) are these changes limited to astrocytes? To address these questions, we captured enriched populations of DLPFC pyramidal neurons and astrocytes from schizophrenia and control subjects using laser capture microdissection and assessed expression of adenosine system components using qPCR. Interestingly, we found changes in enriched populations of astrocytes and neurons spanning metabolic and catabolic pathways. Ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1) and ENTPD2 mRNA levels were significantly decreased (p < 0.05, n = 16 per group) in enriched populations of astrocytes; in pyramidal neurons equilibrative nucleoside transporter 1 (ENT1) and adenosine A

Topics: 5'-Nucleotidase; Adenosine; Adenosine Kinase; Adenosine Triphosphatases; Adult; Aged; Animals; Antipsychotic Agents; Astrocytes; Equilibrative Nucleoside Transporter 1; Female; Frontal Lobe; Gene Expression; GPI-Linked Proteins; Haloperidol; Humans; Male; Middle Aged; Pyramidal Cells; Rats, Sprague-Dawley; Receptors, Purinergic P1; RNA, Messenger; Schizophrenia; Young Adult

An emerging theory of schizophrenia postulates that hypofunction of adenosine signaling may contribute to its pathophysiology. This study was designed to test the "adenosine hypothesis" of schizophrenia and to evaluate focal adenosine-based strategies for therapy. We found that augmentation of adenosine by pharmacologic inhibition of adenosine kinase (ADK), the key enzyme of adenosine clearance, exerted antipsychotic-like activity in mice. Further, overexpression of ADK in transgenic mice was associated with attentional impairments linked to schizophrenia. We observed that the striatal adenosine A2A receptor links adenosine tone and psychomotor response to amphetamine, an indicator of dopaminergic signaling. Finally, intrastriatal implants of engineered adenosine-releasing cells restored the locomotor response to amphetamine in mice overexpressing ADK, whereas the same grafts placed proximal to the hippocampus of transgenic mice reversed their working memory deficit. This functional double dissociation between striatal and hippocampal adenosine demonstrated in Adk transgenic mice highlights the independent contributions of these two interconnected brain regions in the pathophysiology of schizophrenia and thus provides the rationale for developing local adenosine augmentation therapies for the treatment of schizophrenia.

Topics: Adenosine; Adenosine Kinase; Amphetamines; Animals; Antipsychotic Agents; Basal Ganglia; Cell Transplantation; Cells, Cultured; Cognition Disorders; Cricetinae; Disease Models, Animal; Endophenotypes; Hippocampus; Mice; Mice, Inbred C57BL; Mice, Transgenic; Morpholines; Psychotic Disorders; Pyrimidines; Receptor, Adenosine A2A; Schizophrenia; Schizophrenic Psychology