Tomoyuki Kanda

KF17837: A novel selective adenosine A2A receptor antagonist with anticataleptic activity

KF17837 is a novel selective adenosine A2A receptor antagonist. Oral administration of KF17837 (2.5, 10.0 and 30.0 mg/kg) significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A2A receptor agonist, CGS 21680 (10 micrograms), in a dose-dependent manner. KF17837 also reduced the catalepsy induced by haloperidol (1 mg/kg i.p.) and by reserpine (5 mg/kg i.p.). These anticataleptic effects were exhibited dose dependently at doses from 0.625 and 2.5 mg/kg p.o., respectively. Moreover, KF17837 (0.625 mg/kg p.o.) potentiated the anticataleptic effects of a subthreshold dose of L-3,4-dihydroxyphenylalanine (L-DOPA; 25 mg/kg i.p.) plus benserazide (6.25 mg/kg i.p.). These results suggested that KF17837 is a centrally active adenosine A2A receptor antagonist and that the dopaminergic function of the nigrostriatal pathway is potentiated by adenosine A2A receptor antagonists. Furthermore, KF17837 may be a useful drug in the treatment of parkinsonism.

Adenosine A2A antagonists with potent anti-cataleptic activity

Abstract Structure-activity relationship of 8-styrylxanthines for in vivo adenosine A2A antagonism were explored. Diethyl substitution both at the 1- and 3-position was found to dramatically potentiate the anti-cataleptic activity.

Inhibition by topiramate of seizures in spontaneously epileptic rats and DBA/2 mice

The effects of topiramate, a novel antiepileptic drug, on tonic and absence-like seizures in spontaneously epileptic rats (SER; zi/zi, tm/tm) and on sound-induced seizures in DBA/2 mice were investigated. Topiramate (20 and 40 mg/kg i.p.) inhibited both tonic and absence-like seizures in a dose-dependent manner, whereas phenytoin (20 mg/kg i.p.) and zonisamide (40 mg/kg i.p.) inhibited only the tonic seizures. The inhibitory effects of topiramate on absence-like seizures were antagonized by pretreatment with haloperidol (0.5 mg/kg i.p.), but those on the tonic seizures remained unaffected. Topiramate inhibited sound-induced seizures in DBA/2 mice (ED50 = 8.6 mg/kg p.o.). These findings suggest that topiramate may be effective for treatment of both convulsive and absence seizures of human epilepsy. The inhibitory effect of topiramate on absence-like seizures in SER may be mediated through the central dopaminergic system.

Topiramate reduces abnormally high extracellular levels of glutamate and aspartate in the hippocampus of spontaneously epileptic rats (SER)

The spontaneously epileptic rat (SER), a double mutant, manifests both tonic and absence-like seizures. The effect of topiramate, a novel antiepileptic drug, on the extracellular levels of excitatory amino acids (EAA) in the hippocampus of SER was investigated using in vivo microdialysis. The basal levels of glutamate and aspartate in dialysates of hippocampus in SER were 2- to 3-fold higher than those in normal Wistar rats. Both the dose-response relationship and the time course of the suppression of tonic seizures by topiramate were similar to the attenuation of glutamate level in SER. Topiramate (40 mg/kg i.p.) significantly (P < 0.05) reduced both glutamate and aspartate levels in SER while showing no effect on normal Wistar rats. These findings suggest that topiramate reduces abnormally high extracellular levels of glutamate and aspartate in the hippocampus of SER. This effect may, at least in part, be related to the anticonvulsant activity of topiramate.

Effect of a centrally active angiotensin-converting enzyme inhibitor, perindopril, on cognitive performance in a mouse model of Alzheimer's disease.

Angiotensin-converting enzyme (ACE) inhibitors have clinically been widely used as anti-hypertensive agents. In the present study, we compared the effects of a centrally active ACE inhibitor, perindopril, with those of non-centrally active ACE inhibitors, imidapril and enalapril, on cognitive performance in amyloid beta(Abeta) (25-35)-injected mice, a rodent model of Alzheimers disease. We also determined the brain ACE activity in order to elucidate the relationship between the cognitive function and ACE inhibition in the brain. Abeta(25-35)-injected mice showed a cognitive impairment in spontaneous alteration and object recognition tests, the indices of immediate working memory and relatively long-term recognition memory, respectively. As indicated by these tests, the oral administration of perindopril (0.1, 0.3 or 1mg/kg/day) significantly reversed the cognitive impairment in these mice, whereas neither imidapril (0.3, 1 or 3mg/kg/day) nor enalapril (1, 3 or 10mg/kg/day) had any effect on cognitive performance. Perindopril (1mg/kg/day), imidapril (3mg/kg/day), or enalapril (10mg/kg/day) all inhibited the plasma ACE activities by more than 90%. Using the same dosing regimen, only perindopril inhibited the brain ACE activities by more than 50%, whereas imidapril and enalapril showed much less potent effects. These results suggest that perindopril ameliorated the cognitive impairment in the Alzheimers disease model mice through the inhibition of brain ACE activity, but not peripheral ACE activity. Based on our observations, we concluded that a centrally active ACE inhibitor, perindopril, may therefore have a beneficial effect on Alzheimers disease as well as hypertension.

Effects of the adenosine A2A antagonist istradefylline on cognitive performance in rats with a 6-OHDA lesion in prefrontal cortex

RationaleAltered cognitive function is a common feature of both the early and later stages of Parkinson’s disease (PD) that involves alterations in cortical dopamine content. Adenosine A2A antagonists, such as istradefylline, improve motor function in PD, but their effect on cognitive impairment has not been determined.ObjectiveThe present study investigated whether impairment of working memory due to the loss of dopaminergic input into the prefrontal cortex (PFC) is reversed by administration of istradefylline. We also evaluated whether A2A antagonist administration modulates dopamine levels in the PFC.MethodsBilateral lesions of the dopaminergic input to the PFC were produced in rats using 6-hydroxydopamine (6-OHDA). Cognitive performance was evaluated using an object recognition task and delayed alternation task. The effects of istradefylline, donepezil and methamphetamine on cognitive performance were examined. In addition, the effect of istradefylline on extracellular dopamine levels in the PFC was studied.ResultsPFC dopamine levels and cognitive performance were significantly reduced by 6-OHDA lesioning. Istradefylline, donepezil and methamphetamine improved cognitive performance of PFC-lesioned rats. Istradefylline increased dopamine levels in the PFC in both normal and PFC-lesioned rats.ConclusionsPFC dopaminergic input plays an important role in working memory performance. Blockade of A2A receptors using istradefylline reverses the changes in cognitive function, and this may be due to an increase in PFC dopamine content. Adenosine A2A receptor antagonists not only improve motor performance in PD but may also lead to improved cognition.

Effect of a centrally active angiotensin converting enzyme inhibitor, perindopril, on cognitive performance in chronic cerebral hypo-perfusion rats.

We have previously demonstrated that perindopril, an angiotensin-converting enzyme (ACE) inhibitor, ameliorated the cognitive deficits in Alzheimers disease model animals, independently of its anti-hypertensive effect. In this study, we again investigated the effects of perindopril on cognitive function in a vascular dementia model animal, comparing it with other ACE inhibitors. We also determined ACE activity in the brain and extracellular acetylcholine (ACh) concentration in the perirhinal cortex in order to elucidate the mechanism(s) responsible for the effects of these ACE inhibitors on cognitive function. Perindopril was suggested to be more centrally active than imidapril and enalapril, in consideration of the relative distribution of their active metabolites in the brain. This property was at least partially attributed to the lipophilicity of the compound. While the 3 day treatment with perindopril, imidapril or enalapril lowered blood pressure to the same level in spontaneous hypertensive rats, only perindopril reversed the decline in the recognition index in chronic cerebral hypo-perfusion rats, regarded as an animal model of vascular dementia, during an object recognition task. Using the same dosing regimen, perindopril inhibited the brain ACE activities of rats more than imidapril or enalapril. Moreover, a single treatment with perindopril enhanced the extracellular level of ACh in the perirhinal cortex of normal rats. Therefore, we confirmed that only centrally active ACE inhibitors, such as perindopril, can inhibit the ACE in the brain, augmenting cholinergic neurotransmission and thereby ameliorating cognitive impairment in the animal model of vascular dementia.

Antidepressant-like activity of the adenosine A2A receptor antagonist, istradefylline (KW-6002), in the forced swim test and the tail suspension test in rodents

RATIONALE Depression is common in Parkinsons disease (PD) but its response to classical antidepressants is not clear. The adenosine A2A antagonist istradefylline is effective in the treatment of the motor symptoms of PD but inhibition of the adenosine A2A receptor may also induce antidepressant-like effects. OBJECTIVE We have investigated whether istradefylline might be effective in treating depression in PD using the forced swimming test (FST) and the tail suspension test (TST) in rodents. RESULTS Istradefylline significantly decreased immobility time in the FST in both rats and mice (0.16mg/kg and higher) with comparable efficacy to an equivalent dose of the tricyclic antidepressants, desipramine and imipramine. Both 8-OH-DPAT (5-HT1A agonist) and quinpirole (D2 agonist) also reduced the immobility time. The istradefylline-induced reduction of immobility time was attenuated by corticosterone. In addition, the combined use of a sub-threshold dose of istradefylline and the serotonin-noradrenaline reuptake inhibitor venlafaxine ameliorated depression-like behavior in the mouse FST. In the mouse TST, istradefylline (0.08mg/kg and higher) decreased immobility time. Moreover, co-administration of istradefylline with paroxetine or fluoxetine (selective serotonin reuptake inhibitors) or deprenyl (MAO-B inhibitor) at doses that did not show antidepressant-like effects when administered alone, resulted in a significant reduction in immobility time. CONCLUSIONS Istradefylline alone or co-administered with currently available antidepressants, may be useful for the treatment of depression as well as motor symptoms of PD. Its effects might be, at least in part, attributable to modulation of hypothalamic-pituitary-adrenal axis.

Involvement of adenosine A2A receptors in depression and anxiety.

When administered to normal healthy patients, a nonselective adenosine A1/A2A antagonist, caffeine, tended to improve anxiety and depression at low doses and to exacerbate anxiety at high doses. Caffeine also appears to enhance anxiety-related symptoms in patients with panic disorder, and A2A receptor-deficient mice have been reported to exhibit higher anxiety-like behaviors, as well as a lower incidence of depression-like behaviors. Some selective A2A antagonists were reported to ameliorate anxiety-like behaviors in rodents, while others did not affect these behaviors. In addition, most A2A antagonists showed inhibitory effects on depression-like behaviors. The mechanisms underlying the relationship between A2A receptor antagonists and anxiety and depression remain unclear at the present time, although many studies have produced hypotheses. Given that a selective A2A receptor antagonist has recently become available for use in humans, research on the role of A2A receptors in the treatment of mental illness should progress in the near future.

Antidepressant activity of the adenosine A2A receptor antagonist, istradefylline (KW-6002) on learned helplessness in rats

RationaleIstradefylline, an adenosine A2A receptor antagonist, improves motor function in animal models of Parkinson’s disease (PD) and in patients with PD. In addition, some A2A antagonists exert antidepressant-like activity in rodent models of depression, such as the forced swim and the tail suspension tests.ObjectiveWe have investigated the effect of istradefylline on depression-like behaviors using the rat learned helplessness (LH) model.ResultsAcute, as well as chronic, oral administration of istradefylline significantly improved the inescapable shock (IES)-induced escape deficit with a degree of efficacy comparable to chronic treatment with the tricyclic antidepressant desipramine and the selective serotonin (5-HT) reuptake inhibitor, fluoxetine. Both the A1/A2A receptor nonspecific antagonist theophylline and the moderately selective antagonist CGS15943, but not the A1 selective antagonist DPCPX, ameliorated the IES-induced escape deficit. The enhancement of escape response by istradefylline was reversed by a local injection of the A2A specific agonist CGS21680 either into the nucleus accumbens, the caudate-putamen, or the paraventricular nucleus of the hypothalamus, but not by the A1 specific agonist R-PIA into the nucleus accumbens. Moreover, neither the 5-HT2A/2C receptor antagonist methysergide or the adrenergic α 2 antagonist yohimbine, nor the β-adrenergic antagonist propranolol, affected the improvement of escape response induced by istradefylline.ConclusionsIstradefylline exerts antidepressant-like effects via modulation of A2A receptor activity which is independent of monoaminergic transmission in the brain. Istradefylline may represent a novel treatment option for depression in PD as well as for the motor symptoms.