Actions of adenosine A 2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP

Shiozaki, Shizuo; Ichikawa, S.; Nakamura, Junzo; Kitamura, Shigeto; Yamada, Koji; Kuwana, Yoshihisa

doi:10.1007/s002130051146

Cited by 204 publications

(125 citation statements)

References 26 publications

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“…The longterm utility of Trk antagonists may be limited by their effects on the maintenance of neuromuscular junction integrity (Gonzalez et al, 1999) and learning and memory (Korte et al, 1996;Messaoudi et al, 2002;Pang et al, 2004). Adenosine A2a receptor antagonists have been shown to be neuroprotective agents in animal models of parkinsonism (Shiozaki et al, 1999;Koga et al, 2000;Ikeda et al, 2002;Fink et al, 2004). Potential adverse effects on inflammation (Ohta and Sitkovsky, 2001;Thiel et al, 2005) and coronary artery vasoregulation (Belardinelli et al, 1998) have not limited their safe use in humans with Parkinson's disease (Bara-Jimenez et al, 2003;Kase et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Protecting Motor Neurons from Toxic Insult by Antagonism of Adenosine A2a and Trk Receptors

Mojsilovic-Petrovic¹,

Jeong²,

Crocker³

et al. 2006

J. Neurosci.

133

125

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The death of motor neurons in amyotrophic lateral sclerosis (ALS) is thought to result from the interaction of a variety of factors including excitotoxicity, accumulation of toxic proteins, and abnormal axonal transport. Previously, we found that the susceptibility of motor neurons to excitotoxic insults can be limited by inhibiting signals evoked by brain-derived neurotrophic factor (BDNF) activation of the receptor tyrosine kinase B (TrkB). Here we show that this can be achieved by direct kinase inhibition or by blockade of a transactivation pathway that uses adenosine A2a receptors and src-family kinases (SFKs). Downstream signaling cascades (such as mitogen-activated protein kinase and phosphatidylinositol-3 kinase) are inhibited by these blockers. In addition to protecting motor neurons from excitotoxic insult, these agents also prevent toxicity that follows from the expression of mutant proteins (G85R superoxide dismutase 1; G59S p150 glued ) that cause familial motor neuron disease. TrkB, adenosine A2a receptors, and SFKs associate into complexes in lipid raft and nonlipid raft membranes and the signaling from lipids rafts may be particularly important because their disruption by cholesterol depletion blocks the ability of BDNF to render motor neurons vulnerable to insult. The neuroprotective versatility of Trk antagonism suggests that it may have broad utility in the treatment of ALS patients.

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Section: Discussionmentioning

confidence: 99%

Protecting Motor Neurons from Toxic Insult by Antagonism of Adenosine A2a and Trk Receptors

Mojsilovic-Petrovic¹,

Jeong²,

Crocker³

et al. 2006

J. Neurosci.

133

125

View full text Add to dashboard Cite

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“…This has been shown in several experimental models including rodents pretreated with D 2 receptor antagonists, reserpine, 6-OH-dopamine or MPTP or after genetic inactivation of D 2 receptors (Kanda et al, 1994;Pollack and Fink, 1995;Shiozaki et al, 1999;Ward and Dorsa, 1999;Chen et al, 2001, Ferré et al, 2001Hauber et al, 2001;Wardas et al, 2001) or MPTP-treated monkeys (Kanda et al, 1998;Grondin et al, 1999). Reserpinized mice, rats with unilateral 6-OH-dopamine lesions and MPTP-treated monkeys are well-established validated models of Parkinson's disease.…”

Section: Adenosine a 2a Receptors In The Ventral Striatum And The Acumentioning

confidence: 92%

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry

Ferré

Diamond

Goldberg

et al. 2007

Progress in Neurobiology

128

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Adenosine A 2A receptors localized in the dorsal striatum are considered as a new target for the development of antiparkinsonian drugs. Co-administration of A 2A receptor antagonists has shown a significant improvement of the effects of L-DOPA. The present review emphasizes the possible application of A 2A receptor antagonists in pathological conditions other than parkinsonism, including drug addiction, sleep disorders and pain. In addition to the dorsal striatum, the ventral striatum (nucleus accumbens) contains a high density of A 2A receptors, which presynaptically and postsynaptically regulate glutamatergic transmission in the cortical glutamatergic projections to the nucleus accumbens. It is currently believed that molecular adaptations of the cortico-accumbens glutamatergic synapses are involved in compulsive drug seeking and relapse. Here we review recent experimental evidence suggesting that A 2A antagonists could become new therapeutic agents for drug addiction. Morphological and functional studies have identified lower levels of A 2A receptors in brain areas other than the striatum, such as the ventrolateral preoptic area of the hypothalamus, where adenosine plays an important role in sleep regulation. Although initially believed to be mostly dependent on A 1 receptors, here we review recent studies that demonstrate that the somnogenic effects of adenosine are largely mediated by hypothalamic A 2A receptors. A 2A receptor antagonists could therefore be considered as a possible treatment for narcolepsy and other sleep-related disorders. Finally, nociception is another adenosine-regulated neural function previously thought to mostly involve A 1 receptors. Although there is some conflicting literature on the effects of agonists and antagonists, which may partly be due to the lack of selectivity of available drugs, the studies in A 2A receptor knockout mice suggest that A 2A receptor antagonists might have some therapeutic potential in pain states, in particular where high intensity stimuli are prevalent.

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“…Therefore, inhibition of A2A receptors seems to be a potential target for neuroprotection in PD [273,274]. Indeed, in rodent models of PD, A2A antagonism exerts Anti-parkinsonian actions [272,275,276]. The highest expression of adenosine A2A…”

Section: Adenosine Receptors In Pdmentioning

confidence: 99%

Restoration of Mitochondrial Dysfunction in 6-Hydroxydopamine Induced Parkinson’s disease: a Complete Review

Mehan¹,

Kaur²,

Dudi³

et al. 2017

Open J Parkinsons Dis Treatm

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Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by neuronal cell death in the specifi c brain region like basal ganglia, cerebral cortex and hippocampus. Symptoms associated with PD patients are rigidity, akathesia, tremor, postural imbalance, cognitive and memory dysfunctions. Pathological hallmarks are dopaminergic neuronal degeneration, neuro-infl ammation, oxidative stress, free radical generation. In the typical Parkinson's disease model, 6-Hydroxydopamine (6-OHDA) is delivered unilaterally by stereotactic injection into the SNc (substantia nigra pars-compacta) or the striatum mimics the PD symptoms. In addition, it has been shown that 6-OHDA is toxic to complex I & IV of the mitochondrial respiratory chain, leading to subsequent respiratory inhibition and further processed ATP depletion, oxidative stress and neuro-infl ammation. Forskolin (FSK), a diterpene natural plant phytochemical obtained from (Coleus Forskohli), a potent direct activator of adenyl cyclase (AC) enzyme which further activates cAMP/PK A /CREB pathway. FSK mediated activation of AC/cAMP/PK A / CREB pathway is responsible for various neuroprotective mechanisms Based on important and versatile role of FSK, the present study has been designed to investigate the role of cAMP mediated CREB activation in 6-hydroxydopamine induced mitochondrial associated neurotoxicity in rats. Further the studies are extended to understand the disease pathogenesis and to investigate and discuss the various possible central mechanisms involved in the effect of such targets using behavioral paradigm and biochemical markers of neurodegeneration.

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Actions of adenosine A 2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP

Abstract: To our knowledge, KW-6002 is the most potent and orally active adenosine A2A receptor antagonist in experimental models of Parkinson's disease, and may offer a new therapeutic approach to the treatment of Parkinson's disease.

Cited by 204 publications

References 26 publications

Protecting Motor Neurons from Toxic Insult by Antagonism of Adenosine A2a and Trk Receptors

Protecting Motor Neurons from Toxic Insult by Antagonism of Adenosine A2a and Trk Receptors

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry

Restoration of Mitochondrial Dysfunction in 6-Hydroxydopamine Induced Parkinson’s disease: a Complete Review

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