CHRONIC LOW-DOSE CAFFEINE TREATMENT PROTECTS HIPPOCAMPAL LAYER CA1 IN THE LITHIUM-PILOCARPINE MODEL (Li-Pilo) OF EPILEPSY BUT DOES NOT PREVENT EPILEPTOGENESIS
Abstract number :
2.119
Submission category :
Year :
2003
Submission ID :
2068
Source :
www.aesnet.org
Presentation date :
12/6/2003 12:00:00 AM
Published date :
Dec 1, 2003, 06:00 AM
Authors :
Marie-Aude Rigoulot, Arielle Ferrandon, Estelle Koning, Astrid Nehlig U405, INSERM, Strasbourg
The Li-Pilo model reproduces the main characteristics of human temporal lobe epilepsy. After status epilepticus (SE), rats exhibit a latent seizure-free phase followed by a chronic phase during which spontaneous recurrent seizures occur. Extensive damage is present in hippocampus, thalamus, amygdala and ventral cortices. Caffeine acts as an antagonist of adenosine receptors, mainly A[sub]1[/sub] and A[sub]2a, [/sub]that are involved in the release of several neurotransmitters, including glutamate and GABA. Moreover, a long-term exposure to a low-dose of caffeine has been shown to be neuroprotective in different models of ischemia. Therefore the neuroprotective and antiepileptogenic effects of a chronic low-dose of caffeine were investigated in this model.
Adult Sprague-Dawley male rats were subjected to SE by injection of LiCl (3meq/kg) followed 20 h later by pilocarpine (25 mg/kg). Animals received two injections of diazepam (DZP, 2.5 then 1 mg/kg) at 2 h and 10 h of SE. In a subset of rats (lipilo-caffeine), caffeine (0.3 g/L) dissolved in drinking water was available from 15 days before the induction of SE until 7 days after SE. Another group of rats subjected to SE received plain tap water (lipilo-water). Neuronal damage was assessed 7 days after SE by performing cell counting on thionine-stained sections. Occurrence of SRS was video-recorded for 10 h per day in a separate group of rats.
In lipilo-water rats, the number of neurons was dramatically reduced after SE in all subregions of hippocampus, layers II to IV of ventral cortices, medial and lateral thalamus and amygdala. In lipilo-caffeine rats, the hippocampus was partly neuroprotected : almost no damage was observed in CA1, and in hilus neuronal loss was slightly although significantly reduced. In layer III of piriform cortex, lipilo-caffeine rat showed a worsening in damage. All the rats developed SRS with a similar latency (19 [plusmn] 7 days in pilo-water rats vs 17[plusmn] 9 days in pilo-caffeine rats).
A chronic low dose of caffeine displays potent neuroprotective properties in CA1, but does not interfere with epileptogenesis. This suggests that damage in area CA1 does not seem to play a major role in epileptogenesis. This study confirms the data of a previous study using topiramate which also protected CA1 but did not prevent the occurrence of epilepsy. Pharmacological studies in progress indicate that the neuroprotective effects of a chronic low dose of caffeine observed in this study, are mediated by its antagonistic effects on adenosine A[sub]1[/sub] receptors.
[Supported by: INSERM U405]