The functional anatomy and pathology of lithium-pilocarpine and high-dose pilocarpine seizures

Clifford, David B.; Olney, John W.; Maniotis, Andrew J.; Collins, Ruth; Zorumski, Charles F.

doi:10.1016/0306-4522(87)90171-0

Cited by 346 publications

(201 citation statements)

References 25 publications

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“…In these prior studies, cell killing was observed in the RSC and in several other regions of the rat brain. It was not accompanied by definite seizure activity, and was not as fulminating and widespread as reactions we have observed following treatment of adult rats with very high doses of pilocarpine, or with pilocarpine plus lithium [7]. The latter reactions are excitotoxic in nature, are invariably accompanied by prolonged seizure activity, and selectively kill neuronal populations throughout specific neural networks that have received the brunt of the seizure discharge activity [48].…”

Section: Disseminatedmentioning

confidence: 89%

Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain

Creeley

Wozniak

Nardi

et al. 2008

Neurobiology of Aging

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The NMDA antagonist, memantine (Namenda), and the cholinesterase inhibitor, donepezil (Aricept), are currently being used widely, either individually or in combination, for treatment of Alzheimer's disease (AD). NMDA antagonists have both neuroprotective and neurotoxic properties; the latter is augmented by drugs, such as pilocarpine, that increase cholinergic activity. Whether donepezil, by increasing cholinergic activity, might augment memantine's neurotoxic potential has not been investigated. In the present study, we determined that a dose of memantine (20 mg/kg ip), considered to be in the therapeutic (neuroprotective) range for rats, causes a mild neurotoxic reaction in the adult rat brain. Co-administration of memantine (20 or 30 mg/kg) with donepezil (2.5 to 10mg/kg) markedly potentiated this neurotoxic reaction, causing neuronal injury at lower doses of memantine, and causing the toxic reaction to become disseminated and lethal to neurons throughout many brain regions. These findings raise questions about using this drug combination in AD, especially in the absence of evidence that the combination is beneficial, or that either drug arrests or reverses the disease process.

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Section: Disseminatedmentioning

confidence: 89%

Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain

Creeley

Wozniak

Nardi

et al. 2008

Neurobiology of Aging

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“…Lithium plus pilocarpine combinations were used to induce SE, because pretreatment of rats with lithium chloride allows the dose of pilocarpine to be decreased, resulting in a lower mortality and a higher percentage of animals exhibiting SE (19). Lithium chloride was injected at a dose of 3 mEq/kg (127 mg/kg) i.p., 19 to 24 h before the administration of pilocarpine.…”

Section: Pilocarpine Treatmentmentioning

confidence: 99%

Effects of the Novel Antiepileptic Drug Levetiracetam on Spontaneous Recurrent Seizures in the Rat Pilocarpine Model of Temporal Lobe Epilepsy

et al. 2002

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Summary:Purpose: Animal models in which seizures are elicited by chemical or electrical means are commonly used for identification and preclinical testing of novel antiepileptic drugs (AEDs). Such models have been successful in discovering all the new AEDs. However, despite the high efficacy of AEDs against elicited seizures in rodent models, a significant proportion of epilepsy patients with spontaneous recurrent seizures is resistant to these drugs. It is not known whether drug testing in rodent models with spontaneous recurrent seizures would yield a more predictive result with respect to AED efficacy in the clinic. This led us to test one of the novel AEDs, levetiracetam (LEV), in a rat model of temporal lobe epilepsy (TLE) with spontaneous recurrent seizures.Methods: Wistar rats were subjected to pilocarpine-induced status epilepticus and recorded for spontaneous recurrent seizures in the months after pilocarpine treatment. A group of rats with frequent spontaneous seizures was used for the drug trial with LEV. The experimental protocol for drug testing in these rats was as follows. For 2 weeks, rats received subcutaneous implantation of osmotic minipumps filled with saline (predrug control period), followed by a 2-week period with implantation of LEV-filled minipumps (drug period), after which pumps were replaced by drug-free pumps for 2 weeks (postdrug control period). The LEV concentration in the pumps during the drug period was adjusted to give daily doses resulting in the maximal plasma concentration range determined previously in patients with TLE during prolonged treatment with LEV. During the 6 weeks of the experiment in epileptic rats, seizures were recorded by video monitoring.Results: Average seizure frequency during the pre-and postdrug control period in a group of eight epileptic rats was 21 and 25 seizures. This was reduced to an average seizure frequency of 8 seizures during the 2 weeks of treatment with LEV. However, the individual response of rats to LEV varied markedly from complete seizure control to no effect at all, although plasma drug levels were within the therapeutic range in all rats. When seizure frequency was separately calculated for the first and second week of treatment, the significant anticonvulsant effect determined in the first week was partially diminished in the second week, suggesting that tolerance may have developed in some of the rats.Conclusions: The data demonstrate that interesting results can be obtained by drug testing in epileptic rats, giving a more realistic prediction of clinical efficacy than results from drug testing in animal models with elicited seizures. Thus, although drug trials in rats with spontaneous recurrent seizures are laborious and time-consuming, such trials should be added to the preclinical characterization of novel AEDs.

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“…KA is a glutamate receptor agonist and pilocarpine is a muscarinic acetylcholine receptor agonist; both agents induce a partial onset SE with secondary generalization. Lithium potentiates the epileptogenic action of pilocarpine (21). Two different drugs were used: DZP and pentobarbital (PTB).…”

Section: Introductionmentioning

confidence: 99%