Repeated treatment with adenosine A1 receptor agonist and antagonist modifies the anticonvulsant properties of CPPene

Sarro, Giovambattista De; Paola, Eugenio Donato Di; Falconi, Umberto; Ferreri, Guido; Sarro, Angela De

doi:10.1016/s0014-2999(96)00746-7

Cited by 13 publications

(5 citation statements)

References 31 publications

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“…Georgiev et al (1993) reported that caffeine and other non-selective xanthines administered chronically offer significant protection against NMDA-induced seizures. Recent data show that the effects of chronically administered compounds acting at the adenosine A 1 and A 2 receptors are diametrically opposed to those reported following their acute administration (Von Lubitz et al 1994;Adami et al1995;De Sarro et al 1996b). Surely all these observations make the subject quite complex.…”

Section: Discussionmentioning

confidence: 99%

Convulsant effects of some xanthine derivatives in genetically epilepsy-prone rats

Sarro¹,

Grasso

Zappalà

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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The behavioural and electrocorticographic (ECoG) convulsant effects of several xanthine derivatives injected intraperitoneally (i.p.) were studied in genetically-epilepsy prone rats. The aim of the study was to evaluate the relationship among convulsant potency, molecular structure and lipophilicity of some xanthines. Animals were injected i.p. with various doses (250-1000 micromol/kg) and a different convulsant potency was observed among the various xanthines tested. IBMX (3-isobutyl-1-methylxanthine), theophylline (1,3-dimethylxanthine) and caffeine (1,3,7-trimethylxanthine) induced an epileptogenic pattern that consisted in an initial phase characterized by wet-dog shakes followed by head tremor, nodding, clonic convulsion and they appeared to be the most potent xanthines among those studied. During seizures, the electrocortical activity was usually characterized by single or multiple sharp- or spike-wave episodes followed by polyspike discharges. After the highest doses of IBMX, theophylline and caffeine, the animals react with falling down, transient tonic clonic seizures, escape response and generalized seizures followed by post-ictal period. Equimolar doses of 8-chlorotheophylline and theobromine (3,7-dimethylxanthine) produced less evident epileptic responses in comparison to previous compounds, whereas no epileptic signs were observed following the administration of enprofylline (3-propylxanthine), etofylline [7-(2-hydroxyethyl)theophylline], diprophylline [7-(2,3-dihydroxy-propyl)theophylline] and doxofylline [7-(1,3-dioxolan-2-ylmethyl) theophylline]. Lipophylicity of the compounds was determined, but no convincing correlations were found between the rank order of lipophilicities and the convulsant potencies of the compounds studied. On the other hand, structure-activity relationship was also investigated. We suggest that the substitution pattern on the xanthine nucleus may explain, in part, the different convulsant potency of the compounds studied. Furthermore, a selective antagonism of adenosine subtype receptors should be considered.

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Section: Discussionmentioning

confidence: 99%

Convulsant effects of some xanthine derivatives in genetically epilepsy-prone rats

Sarro¹,

Grasso

Zappalà

et al. 1997

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Moreover the activation of adenosine receptor A1R with CPA enhances neurotoxicity caused by kainate in cortical cultures neurons [42]. Besides adenosine did not promote Purkinje cell survival in rat cerebellar culture [43] and repeated treatment with the analogue 2-chloro-N6-cyclopentyladenosine, a selective adenosine A1 receptor agonist, decreases the anticonvulsant properties of 3-(2 carboxypiperazine-4y) propenyl-1-phosphonic acid (CPPene) against audiogenic seizures [44].…”

Section: H]-ccpa and [ 3 H]-mk 801 Bindingmentioning

confidence: 99%

Differential Expression of Cerebellar Metabotropic Glutamate Receptors mGLUR2/3 and mGLUR4a after the Administration of a Convulsant Drug and the Adenosine Analogue Cyclopentyladenosine

et al. 2007

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Metabotropic glutamate receptors (mGluR) play a role in synaptic transmission, neuronal modulation and plasticity but their action in epileptic activity is still controversial. On the other hand adenosine acts as a neuromodulator with endogenous anticonvulsive properties. Since cerebellum from epileptic patients has shown neuronal damage, sometimes associated with Purkinje cells loss, we have explored the effect of repetitive seizures on two types of mGluR in the cerebellum. Seizures were induced by the convulsant drug 3-mercaptopropionic acid (MP) and the effect of the adenosine analogue cyclopentyladenosine (CPA) alone or before MP administration (CPA+MP) were also evaluated. The expression of the receptors subtypes 2/3 (mGluR2/3) and 4a (mGluR4a) was assessed by immunocitochemistry. Granular cell layer was labeled with mGluR2/3 antibody and increased immunoreactivity was observed after MP (60%), CPA (53%) and CPA + MP (85%) treatments. Control cerebellum slices showed mGluR4a reactivity around Purkinje cells, while MP, CPA and CPA+MP treatment decreased this immunostaining. Repetitive administration of MP and CPA induces an increased cerebellar mGluR2/3 and a decreased mGluR4a immunostaining, suggesting a distinct participation of both receptors that may be related to the type of cell involved. A protective action and /or an apoptotic effect may not be discarded. CPA repetitive administration although increase seizure latency, cannot prevent seizure activity.

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“…Yet, despite highly encouraging laboratory results, several factors, e.g., bradycardia and hypotension, mitigated against acute clinical implementation of adenosine Al receptor agonists (Williams, 1993). Moreover, the recently described phenomenon of treatment-dependent inversion of the in vivo therapeutic effect, where acute treatment leads to the outcome that is opposite to that seen after chronic exposure (Von Lubitz et al, 1994a,b;De Sarro et al, 1996), warranted equal caution in chronic application of this class of drugs. Interestingly, dependence of the therapeutic outcome on the treatment regimen (i.e., acute vs. chronic) has been encountered during studies involving adenosine A 2A and A 3 receptors as well (Von Lubitz et al, 1994b).…”

Section: Introductionmentioning

confidence: 99%

Protection against ischemic damage by adenosine amine congener, a potent and selective adenosine A1 receptor agonist

Lubitz¹,

Lin

Bischofberger

et al. 1999

European Journal of Pharmacology

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Although the selectivity and potency of adenosine amine congener (ADAC) at adenosine A 1 receptors are similar to other highly selective agonists at this receptor type, the chemical structure of the N 6 substituent is completely different. We now demonstrate that the characteristics of the therapeutic profile of ADAC are distinct from those observed during our previous studies of adenosine A 1 receptor agonist-mediated neuroprotection. Most significantly, chronic treatment with low microgram doses of ADAC (25-100 µg/kg) protects against both mortality and neuronal damage induced by 10 min bilateral carotid occlusion in gerbils. At higher chronic doses, the statistical significance of the protective effect is lost. Acute preischemic administration of the drug at 75-200 µg/kg also results in a statistically significant reduction of postischemic mortality and morbidity. These data indicate that, contrary to other adenosine A 1 receptor agonists whose chronic administration enhances postocclusive brain damage, ADAC may be a promising agent in treatment of both acute (e.g., cerebral ischemia) and chronic (seizures) disorders of the central nervous system in which adenosine A 1 receptors appear to be involved.

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Repeated treatment with adenosine A1 receptor agonist and antagonist modifies the anticonvulsant properties of CPPene

Cited by 13 publications

References 31 publications

Convulsant effects of some xanthine derivatives in genetically epilepsy-prone rats

Convulsant effects of some xanthine derivatives in genetically epilepsy-prone rats

Differential Expression of Cerebellar Metabotropic Glutamate Receptors mGLUR2/3 and mGLUR4a after the Administration of a Convulsant Drug and the Adenosine Analogue Cyclopentyladenosine

Protection against ischemic damage by adenosine amine congener, a potent and selective adenosine A1 receptor agonist

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