Atipamezole, an α2-adrenoceptor antagonist, has disease modifying effects on epileptogenesis in rats

Pitkänen, Asla; Narkilahti, Susanna; Bezvenyuk, Zinayida; Haapalinna, Antti; Nissinen, Jari

doi:10.1016/j.eplepsyres.2004.07.005

Cited by 46 publications

(37 citation statements)

References 51 publications

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“…Alpha-2 adrenoceptor stimulation has been thought to delay kindling, and in rats, atipamezole was shown to lower daily seizure frequency [11]. These findings suggest a decreased chance of inducing seizure activity after atipamezole administration.…”

Section: Discussionmentioning

confidence: 52%

Electroencephalographic Recordings in the Canine: Effects of Low Dose Medetomidine or Dexmedetomidine Followed by Atipamezole

Tepper¹,

Shores²

2014

OJVM

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Objectives: 1) To describe electroencephalogram (EEG) appearance in the awake dog and compare these results with EEG recordings after low dose medetomidine (2 µg/kg IV) followed by atipamezole (10 µg/kg, IM); 2) To institute EEG recordings after low dose medetomidine or dexmedetomidine as a standard of practice if focal abnormalities and amplitudes were not significantly altered by pharmaceuticals in Phase 1 of this study. Methods: Electroencephalograms were performed on eight clinical canine patients with suspected intracranial disease involving the prosencephalon. A five lead montage was used to record the EEGs. Each dog had an awake, baseline recording followed by an EEG performed after administration of low dose medetomidine (2 µg/kg IV) then atipamezole (10 µg/kg, IM). In the second phase of this study, the same dose of medetomidine or dexmedetomidine at 1 µg/kg IV and atipamezole (10 µg/kg, IM) were used in the evaluation of 20 clinical patients with suspected neurologic disease. Results: In Phase 1, awake recordings were laced with movement artifacts. After medetomidine and atipamezole, EEG waveforms were slower. Following atipamezole, however, the frequencies were observed to increase with time. Statistical evaluation revealed significantly more artifacts in baseline recordings.No statistically significant change was observed in focal abnormalities or amplitude. In Phase 2, the α2-adrenoreceptor agonists followed by atipamezole without the use of lidocaine produced clinically reliable results. Clinical Significance: Quality and diagnostic electroencephalogram (EEG) recordings are frequently inconvenient to obtain in the awake dog. Movement results in artifacts and dislodged leads. Administration of low dose medetomidine or dexmedetomidine followed by atipamezole reliably reduced the impact of movement artifacts and produced clinically valid EEG recordings in dogs.

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Section: Discussionmentioning

confidence: 52%

Electroencephalographic Recordings in the Canine: Effects of Low Dose Medetomidine or Dexmedetomidine Followed by Atipamezole

Tepper¹,

Shores²

2014

OJVM

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“…Other potential targets include NKCC1 [57,62] and modulators of neuroinflammation, that is, IL-1, COX-2, and transforming growth factor β [63]. Further interesting findings (not discussed in detail here) include 1) administration of decoy oliognucleotides limiting the transcriptional repressor, neuron-restrictive silencer factor (NRSF), which is initiated after SE, resulted in a 70 % reduction in the number of SRS during the ensuing 2 weeks [65]; 2) pharmacological depletion of a microRNA, miR-134, initiated after SE reduced the occurrence of SRS when tested weeks later [66]; and 3) treatment with atipamezole, an α2-adrenergic receptor antagonist, starting 1 week after SE, reduced frequency and severity of SRS tested after wash-out from atipamezole, indicating a disease-modifying effect [67]. Whether it will be possible to prevent epilepsy with just a single drug is still not clear and well-designed studies that compare this approach to a "cocktail" approach are clearly warranted.…”

Section: Discussionmentioning

confidence: 99%

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

White

Löscher²

2014

Neurotherapeutics

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A major unmet medical need is the lack of treatments to prevent (or modify) epilepsy in patients at risk, for example, after epileptogenic brain insults such as traumatic brain injury, stroke, or prolonged acute symptomatic seizures like complex febrile seizures or status epilepticus. Typically, following such brain insults there is a seizure-free interval ("latent period"), lasting months to years before the onset of spontaneous recurrent epileptic seizures. The latent period after a brain insult offers a window of opportunity in which an appropriate treatment may prevent or modify the epileptogenic process induced by a brain insult. A similar latent period occurs in patients with epileptogenic gene mutations. Studies using animal models of epilepsy have led to a greater understanding of the factors underlying epileptogenesis and have provided significant insight into potential targets by which the development of epilepsy may be prevented or modified. This review focuses largely on some of the most common animal models of epileptogenesis and their potential utility for evaluating proposed antiepileptogenic therapies and identifying useful biomarkers. The authors also describe some of the limitations of using animal models in the search for therapies that move beyond the symptomatic treatment of epilepsy. Promising results of previous studies designed to evaluate antiepileptogenesis and the role of monotherapy versus polytherapy approaches are also discussed. Recent data from both models of genetic and acquired epilepsies strongly indicate that it is possible to prevent or modify epileptogenesis, and, hopefully, such promising results can ultimately be translated into the clinic.

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“…The therapeutic window of opportunity after SE is not known, but, depending on the strategy of antiepileptogenesis used, it may be very short (Armstrong et al, 2009). On the other hand, Pitkänen et al (2004) reported a disease-modifying effect of prophylactic treatment with the ␣ 2 -adrenoceptor antagonist atipamezole, when treatment was started 1 week after SE.…”

Section: Discussionmentioning

confidence: 99%

Disease-Modifying Effects of Phenobarbital and the NKCC1 Inhibitor Bumetanide in the Pilocarpine Model of Temporal Lobe Epilepsy

Brandt¹,

Nozadze²,

Heuchert³

et al. 2010

Journal of Neuroscience

164

166

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Accumulating evidence suggests that changes in neuronal chloride homeostasis may be involved in the mechanisms by which brain insults induce the development of epilepsy. A variety of brain insults, including status epilepticus (SE), lead to changes in the expression of the cation-chloride cotransporters KCC2 and NKCC1, resulting in intracellular chloride accumulation and reappearance of immature, depolarizing synaptic responses to GABA A receptor activation, which may critically contribute to the neuronal hyperexcitability underlying epileptogenesis. In the present study, it was evaluated whether prolonged administration of the selective NKCC1 inhibitor, bumetanide, after a pilocarpine-induced SE modifies the development of epilepsy in adult female rats. The antiepileptic drug phenobarbital, either alone or in combination, was used for comparison. Based on pharmacokinetic studies with bumetanide, which showed extremely rapid elimination and low brain penetration of this drug in rats, bumetanide was administered systemically with different dosing protocols, including continuous intravenous infusion. As shown by immunohistochemistry, neuronal NKCC1 expression was markedly upregulated shortly after SE. Prophylactic treatment with phenobarbital after SE reduced the number of rats developing spontaneous seizures and decreased seizure frequency, indicating a disease-modifying effect. Bumetanide did not exert any significant effects on development of spontaneous seizures nor did it enhance the effects of phenobarbital. However, combined treatment with both drugs counteracted several of the behavioral consequences of SE, which was not observed with single drug treatment. These data do not indicate that bumetanide can prevent epilepsy after SE, but the disease-modifying effect of this drug warrants further studies with more lipophilic prodrugs of bumetanide.

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Atipamezole, an α2-adrenoceptor antagonist, has disease modifying effects on epileptogenesis in rats

Cited by 46 publications

References 51 publications

Electroencephalographic Recordings in the Canine: Effects of Low Dose Medetomidine or Dexmedetomidine Followed by Atipamezole

Electroencephalographic Recordings in the Canine: Effects of Low Dose Medetomidine or Dexmedetomidine Followed by Atipamezole

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

Disease-Modifying Effects of Phenobarbital and the NKCC1 Inhibitor Bumetanide in the Pilocarpine Model of Temporal Lobe Epilepsy

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