Focally injected adenosine prevents seizures in the rat

Anschel, David J.; Ortega, Erik; Kraus, Alli C.; Fisher, Robert S.

doi:10.1016/j.expneurol.2004.07.017

Cited by 57 publications

(35 citation statements)

References 6 publications

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“…Dose response studies have shown that intraventricular doses of 50–500 ng adenosine / kg body weight / d provide effective seizure suppression in rodents, whereas doses of up to 5 mg ADO / kg / d were without sedative side effects (Güttinger et al, 2005b; Huber et al, 2001; Li et al, 2008; Li et al, 2007b; Wilz et al, 2008). The therapeutic efficacy of intracranial adenosine has independently been reproduced by Robert Fisher in a study to prevent bicuculline-induced ictal and epileptiform discharges (Anschel et al, 2004). In a recent study from Paul Boon’s group adenosine has been infused with osmotic pumps into epileptic rats in which TLE was induced by systemic KA-induced SE (Van Dycke et al, 2010).…”

Section: Adenosine-dependent Mechanisms and Therapeutic Applicationsmentioning

confidence: 99%

Comorbidities in Neurology: Is adenosine the common link?

Boison

Aronica

2015

Neuropharmacology

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Comorbidities in Neurology represent a major conceptual and therapeutic challenge. For example, temporal lobe epilepsy (TLE) is a syndrome comprised of epileptic seizures and comorbid symptoms including memory and psychiatric impairment, depression, and sleep dysfunction. Similarly, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are accompanied by various degrees of memory dysfunction. Patients with AD have an increased likelihood for seizures, whereas all four conditions share certain aspects of psychosis, depression, and sleep dysfunction. This remarkable overlap suggests common pathophysiological mechanisms, which include synaptic dysfunction and synaptotoxicity, as well as glial activation and astrogliosis. Astrogliosis is linked to synapse function via the tripartite synapse, but astrocytes also control the availability of gliotransmitters and adenosine. Here we will specifically focus on the ‘adenosine hypothesis of comorbidities’ implying that astrocyte activation, via overexpression of adenosine kinase (ADK), induces a deficiency in the homeostatic tone of adenosine. We present evidence from patient-derived samples showing astrogliosis and overexpression of ADK as common pathological hallmark of epilepsy, AD, PD, and ALS. We discuss a transgenic ‘comorbidity model’, in which brain-wide overexpression of ADK and resulting adenosine deficiency produces a comorbid spectrum of seizures, altered dopaminergic function, attentional impairment, and deficits in cognitive domains and sleep regulation. We conclude that dysfunction of adenosine signaling is common in neurological conditions, that adenosine dysfunction can explain comorbid phenotypes, and that therapeutic adenosine augmentation might be effective for the treatment of comorbid symptoms in multiple neurological conditions.

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Section: Adenosine-dependent Mechanisms and Therapeutic Applicationsmentioning

confidence: 99%

Comorbidities in Neurology: Is adenosine the common link?

Boison

Aronica

2015

Neuropharmacology

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“…For example, CGS 21680 was proconvulsant and anticonvulsant in three different animal models [95,273,276,302]. Adenosine decreased or increased epileptic activity in PTZ- [118,204], bicuculline- [117,168], pilocarpine- [216], kainic-acid- [138], Mg 2+ -free [140,219] and penicillin-induced models [120] as well as in the animal model of human absence epilepsy [309] ( Table 4), and focally applied Ado was more effective against penicillin-induced epileptiform activity than intracerebroventricularly injected Ado [120]. In addition, Ado receptor agonists and antagonists as well as nucleoside transport inhibitors may have different effects on seizures in the mature brain compared with the immature brain because of (i) the level and distribution of endogenous Ado, (ii) the affinity of Ado receptors for Ado, (iii) the distribution of Ado receptors and Ado transporters and (iv) the ratio of different types of Ado receptors and, consequently, the physiological and pathophysiological role of Ado in different brain areas may be changed by age [31,57,[310][311][312][313].…”

Section: Adenosine Receptor Agonists and Antagonistsmentioning

confidence: 99%

“…Consequently, increasing the Ado level in the brain by specific inhibitors of nucleoside metabolic enzymes (e.g., ADA and ADK inhibitors) and nucleoside transporters ( Table 2; Fig. 2A and 2B), or by Ado-releasing grafts (in which Ado metabolizing enzymes are inactivated) ( Table 4), ketogenic diets or direct (focal) infusion of Ado (Table 4) may have seizurepreventing/decreasing effects [110,[113][114][115][116][117][118][119][120][121]. Ketamine-induced (intraperitoneal injection) epileptiform activity Decreased epileptiform activity [217] Kindling (rat amygdala) model Seizure suppression [213] Theophylline-induced (intravenous application) seizures Proconvulsant effect [224] Papaverine Bicuculline-induced (rat prepiriform cortex) seizures Anticonvulsant effect [134] Soluflazine Mg 2+ -free condition, electrically-induced (guineapig hippocampal slices) epileptiform activity Decreased epileptiform activity [218] Abbreviations: ADA: adenosine deaminase; ADK: adenosine kinase; BW534U87: …”

Section: Adenosinementioning

confidence: 99%

“…Bicuculline-induced (rat hippocampus) seizures (focally injected Ado by infusion pump into hippocampus) Seizure prevention [117] Kainic acid-induced (intraperitoneal injection) seizures in rats (delivery of Ado by osmotic micropump into hippocampus) Seizure reduction [138] Lithium-pilocarpine-induced status epilepticus in rats (intraperitoneal application of Ado) Protective effect [216] Penicillin-induced (rat cortex) epileptiform activity (intracortical and intracerebroventricular application of Ado) Decreased epileptiform activity [120] Pentylenetetrazole-induced (intraperitoneal injection) seizures in rats Seizure protection [204] Pentylenetetrazole-induced (intraperitoneal injection) seizures in mice Increased seizure latency [118] Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats (animal model of human absence epilepsy) Increased absence epileptic activity [309] 4-aminopyridine-induced (rat hippocampal slices; Mg…”

Section: Direct (Focal) Application Of Adomentioning

confidence: 99%

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The Antiepileptic Potential of Nucleosides

Kovács¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Despite newly developed antiepileptic drugs to suppress epileptic symptoms, approximately one third of patients remain drug refractory. Consequently, there is an urgent need to develop more effective therapeutic approaches to treat epilepsy. A great deal of evidence suggests that endogenous nucleosides, such as adenosine (Ado), guanosine (Guo), inosine (Ino) and uridine (Urd), participate in the regulation of pathomechanisms of epilepsy. Adenosine and its analogues, together with non-adenosine (non-Ado) nucleosides (e.g., Guo, Ino and Urd), have shown antiseizure activity. Adenosine kinase (ADK) inhibitors, Ado uptake inhibitors and Ado-releasing implants also have beneficial effects on epileptic seizures. These results suggest that nucleosides and their analogues, in addition to other modulators of the nucleoside system, could provide a new opportunity for the treatment of different types of epilepsies. Therefore, the aim of this review article is to summarize our present knowledge about the nucleoside system as a promising target in the treatment of epilepsy.

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“…Focally administered small-molecule antiepileptic drugs (such as diazepam and carbamazepine) and inhibitory substances (such as adenosine, GABA, and muscimol) have been demonstrated to prevent seizure generation and inhibit ongoing seizures in animal models (Eder et al, 1997;Stein et al, 2000;Anschel et al, 2004;Fisher and Chen, 2006;Ludvig et al, 2010). However, these agents have a short duration of action because they diffuse from the site of delivery or are biologically inactivated.…”

Section: Introductionmentioning

confidence: 99%

Long-Lasting Attenuation of Amygdala-Kindled Seizures after Convection-Enhanced Delivery of Botulinum Neurotoxins A and B into the Amygdala in Rats

Gąsior

Tang

Rogawski

2013

J Pharmacol Exp Ther

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Botulinum neurotoxins (BoNTs) are well recognized to cause potent, selective, and long-lasting neuroparalytic actions by blocking cholinergic neurotransmission to muscles and glands. There is evidence that BoNT isoforms can also inhibit neurotransmission in the brain. In this study, we examined whether locally delivered BoNT/A and BoNT/B can attenuate kindling measures in amygdala-kindled rats. Male rats were implanted with a combination infusion cannula-stimulating electrode assembly into the right basolateral amygdala. Fully kindled animals received a single infusion of vehicle or BoNT/A or BoNT/B at doses of 1, 3.2, or 10 ng over a 20-minute period by convectionenhanced delivery. Electrographic (EEG) and behavioral kindling measures were determined at selected times during the 3-to 64-day period after the infusion. BoNT/B produced a dose-dependent elevation in after-discharge threshold and duration and a reduction in the seizure stage and duration of behavioral seizures that lasted for up to 50 days after infusion. BoNT/A had similar effects on EEG measures; behavioral seizure measures were also reduced, but the effect did not reach statistical significance. The effects of both toxins on EEG and behavioral measures progressively resolved during the latter half of the observation period. Animals gained weight normally, maintained normal body temperature, and did not show altered behavior. This study demonstrates for the first time that locally delivered BoNTs can produce prolonged inhibition of brain excitability, indicating that they could be useful for the treatment of brain disorders, including epilepsy, that would benefit from long-lasting suppression of neurotransmission within a circumscribed brain region.

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Focally injected adenosine prevents seizures in the rat

Cited by 57 publications

References 6 publications

Comorbidities in Neurology: Is adenosine the common link?

Comorbidities in Neurology: Is adenosine the common link?

The Antiepileptic Potential of Nucleosides

Long-Lasting Attenuation of Amygdala-Kindled Seizures after Convection-Enhanced Delivery of Botulinum Neurotoxins A and B into the Amygdala in Rats

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