Allopurinol augmentation for poorly responsive schizophrenia

Dr, Lara; Mg, Brunstein; Ghisolfi, ES; Mi, Lobato; Belmonte-de-Abreu, Paulo; Souza, Diogo O.

doi:10.1097/00004850-200107000-00008

Cited by 44 publications

(27 citation statements)

References 21 publications

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“…Conventional antipsychotic drugs were not designed to modulate the dopaminergic and glutamatergic systems concomitantly, which might be needed to achieve more efficient treatment of the positive, negative, and cognitive symptoms of schizophrenia; however, manipulating adenosine as an upstream regulator of both dopamine and glutamate might offer such a concomitant treatment approach. A link between adenosine hypofunction and schizophrenia is also supported by clinical evidence: increased enzymatic degradation of adenosine by adenosine deaminase has been detected in patients with schizophrenia (11,12), whereas allopurinol, a purine degradation inhibitor that increases adenosine tone, has shown clinical efficacy as add-on therapy for schizophrenia (13,14).…”

Section: Introductionmentioning

confidence: 95%

Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia

Shen¹,

Singer²,

Lytle³

et al. 2012

J. Clin. Invest.

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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 A 2A 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. IntroductionDespite extensive research over half a century, schizophrenia remains a major health concern, affecting more than one percent of the population. Two hypotheses, those of dopaminergic hyperfunction (1) and glutamatergic hypofunction (2), are widely accepted conceptual frameworks for understanding the pathophysiology of schizophrenia and for the development of drugs for the treatment of either dopamine-related or glutamate-related symptoms of the disease (2, 3). This study addresses a third hypothesis, the "adenosine hypothesis of schizophrenia," which has recently been proposed as a novel concept to integrate the dopaminergic hyperfunction and glutamatergic hypofunction hypotheses (4).The purine ribonucleoside adenosine modulates neurotransmission through activation of 4 types of G protein-coupled adenosine receptors (ARs), A 1 R, A 2A R, A 2B R, and A 3 R, which exert spatially distinct functions within the brain on presynaptic and postsynaptic sites (5, 6). Presynaptically, adenosine regulates the release of both dopamine and glutamate (7,8), whereas the output of dopaminergic and glutamatergic neurotransmission is regulated by heterodimerization of ARs with dopamine and glutamate receptors (9, 10). Through these mechanisms adenosine exerts upstream control over both dopaminergic and glutamatergic signaling. Consequently, any disruption in adenosine homeostasis is expected to affect those 2 transmitter systems, which play fundamental roles in the pathophysiology of schizophrenia. This regulatory function of adenosine might provide a missing link for the functional integration of the dopamine and glutamate hypotheses. Conventional antipsychotic

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Section: Introductionmentioning

confidence: 95%

Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia

Shen¹,

Singer²,

Lytle³

et al. 2012

J. Clin. Invest.

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show abstract

“…Moreover, transgenic mice overexpressing adenosine kinase, a cytosolic ribokinase that phosphorylates the re-uptaken adenosine into 5′-adenosine monophosphate (AMP), show attention impairments linked to SZ, while adenosine augmentation exerts antipsychotic-like activity in mice [11]. In fact, several clinical trials have shown the beneficial effects of drugs that modulate adenosine signalling such as allopurinol and dipyridamole, which increase extracellular adenosine levels by inhibiting its degradation and reuptake, respectively [12][13][14][15][16][17]. Interestingly, caffeine (a non-selective adenosine receptor antagonist) consumption exacerbates psychotic symptoms in SZ patients [18].…”

Section: Introductionmentioning

confidence: 99%

Reduced striatal ecto-nucleotidase activity in schizophrenia patients supports the “adenosine hypothesis”

Aliagas

Villar-Menéndez

Sévigny

et al. 2013

Purinergic Signalling

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Schizophrenia (SZ) is a major chronic neuropsychiatric disorder characterized by a hyperdopaminergic state. The hypoadenosinergic hypothesis proposes that reduced extracellular adenosine levels contribute to dopamine D 2 receptor hyperactivity. ATP, through the action of ecto-nucleotidases, constitutes a main source of extracellular adenosine. In the present study, we examined the activity of ecto-nucleotidases (NTPDases, ecto-5′-nucleotidase, and alkaline phosphatase) in the postmortem putamen of SZ patients (n=13) compared with aged-matched controls (n=10). We firstly demonstrated, by means of artificial postmortem delay experiments, that ectonucleotidase activity in human brains was stable up to 24 h, indicating the reliability of this tissue for these enzyme determinations. Remarkably, NTPDase-attributable activity (both ATPase and ADPase) was found to be reduced in SZ patients, while ecto-5′-nucleotidase and alkaline phosphatase activity remained unchanged. In the present study, we also describe the localization of these ecto-enzymes in human putamen control samples, showing differential expression in blood vessels, neurons, and glial cells. In conclusion, reduced striatal NTPDase activity may contribute to the pathophysiology of SZ, and it represents a potential mechanism of adenosine signalling impairment in this illness.

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“…It has been previously reported that adenosine is a regulator of the bioenergetics network that has been observed to modulate both glutamatergic and dopaminergic neurotransmission. 36 Moreover, Lara et al 37 suggested that dysfunction in purine metabolism would result in decreased levels of adenosinergic activity, which will cause an imbalance between glutamatergic and dopaminergic neurotransmission. This mechanism is accepted as the milestone of the pathophysiology of schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

“…38 Allopurinol, an XO inhibitor, has already been studied as an additional treatment method in schizophrenia patients. 19,37,39 It functions as an inhibitor in the major degradation pathway of purines and is strongly believed to increase levels of purines, including adenosine. 18 In our experimental model, we determined that XO levels were significantly reduced (P = 0.0001) in the paliperidone group.…”

Section: Discussionmentioning

confidence: 99%

Paliperidone regulates intracellular redox system in rat brain: Role of purine mechanism

et al. 2014

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Allopurinol augmentation for poorly responsive schizophrenia

Cited by 44 publications

References 21 publications

Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia

Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia

Reduced striatal ecto-nucleotidase activity in schizophrenia patients supports the “adenosine hypothesis”

Paliperidone regulates intracellular redox system in rat brain: Role of purine mechanism

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