N-methyl-D-aspartate receptor blockade after status epilepticus protects against limbic brain damage but not against epilepsy in the kainate model of temporal lobe epilepsy - PubMed (original) (raw)
N-methyl-D-aspartate receptor blockade after status epilepticus protects against limbic brain damage but not against epilepsy in the kainate model of temporal lobe epilepsy
C Brandt et al. Neuroscience. 2003.
Abstract
Most patients with temporal lobe epilepsy (TLE), the most common type of epilepsy, show pronounced loss of neurons in limbic brain regions, including the hippocampus. The massive neurodegeneration in the hippocampus is known as hippocampal sclerosis, and is considered one of the hallmarks of this type of difficult-to-treat epilepsy. There is a long and ongoing debate on whether this sclerosis is the result of an initial pathological event, such as a status epilepticus (S.E.), stroke or head trauma, which often precedes the development of TLE, or is caused by the spontaneous recurrent seizures (SRS) once epilepsy has developed. At present, pharmacological prevention of limbic sclerosis is not available. In a clinical situation, such prevention would only be possible if delayed cell death developing after an initial pathological event is involved. Assuming that sclerotic brain lesions provoke epileptogenesis and that delayed cell death is involved in these lesions, it should be possible to prevent both the lesions and the epilepsy by a prophylactic treatment after an initial insult such as an S.E. In order to test this hypothesis, we used a rat model of TLE in which limbic brain lesions and epilepsy with SRS develop after a kainate-induced S.E. A single low dose of the N-methyl-D-aspartate (NMDA) receptor blocker dizocilpine (MK-801) significantly reduced the damage in limbic regions, including the hippocampus and piriform cortex, and completely protected several rats from such damage when given after an S.E. of 90 min induced by kainate, strongly suggesting that delayed cell death is involved in the damage. This was substantiated by the use of molecular and immunohistochemical markers of delayed active ("programmed") cell death. However, the neuroprotection by dizocilpine did not prevent the development of SRS after the S.E., suggesting that structures not protected by dizocilpine may play a role in the genesis of SRS or that epileptogenesis is not the consequence of structural lesions in the limbic system. The only brain regions that exhibited neuronal damage in all rats with SRS were the hilus of the dentate gyrus and the mediodorsal thalamus, although treatment with dizocilpine reduced the severity of damage in the latter region. The data indicate that NMDA receptor blockade immediately after a prolonged S.E. is an effective means to reduce the damage produced by a sustained S.E. in several brain regions, including the hippocampus, but show that this partial neuroprotection of the limbic system does not prevent the development of epilepsy.
Similar articles
- Delayed sclerosis, neuroprotection, and limbic epileptogenesis after status epilepticus in the rat.
Ebert U, Brandt C, Löscher W. Ebert U, et al. Epilepsia. 2002;43 Suppl 5:86-95. doi: 10.1046/j.1528-1157.43.s.5.39.x. Epilepsia. 2002. PMID: 12121301 - Expression of heat shock protein-70 and limbic seizure-induced neuronal death in the rat brain.
Zhang X, Boulton AA, Yu PH. Zhang X, et al. Eur J Neurosci. 1996 Jul;8(7):1432-40. doi: 10.1111/j.1460-9568.1996.tb01605.x. Eur J Neurosci. 1996. PMID: 8758950 - Non-NMDA but not NMDA blockade at deep prepiriform cortex protects against hippocampal cell death in status epilepticus.
Kawaguchi K, Simon RP. Kawaguchi K, et al. Brain Res. 1997 Apr 4;753(1):152-6. doi: 10.1016/s0006-8993(97)00007-3. Brain Res. 1997. PMID: 9125442 - Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro.
Avoli M, D'Antuono M, Louvel J, Köhling R, Biagini G, Pumain R, D'Arcangelo G, Tancredi V. Avoli M, et al. Prog Neurobiol. 2002 Oct;68(3):167-207. doi: 10.1016/s0301-0082(02)00077-1. Prog Neurobiol. 2002. PMID: 12450487 Review. - What is animal experimentation telling us about new drug treatments of status epilepticus?
Nehlig A. Nehlig A. Epilepsia. 2007;48 Suppl 8:78-81. doi: 10.1111/j.1528-1167.2007.01358.x. Epilepsia. 2007. PMID: 18330008 Review.
Cited by
- Effect of age on kainate-induced seizure severity and cell death.
McCord MC, Lorenzana A, Bloom CS, Chancer ZO, Schauwecker PE. McCord MC, et al. Neuroscience. 2008 Jun 26;154(3):1143-53. doi: 10.1016/j.neuroscience.2008.03.082. Epub 2008 Apr 11. Neuroscience. 2008. PMID: 18479826 Free PMC article. - Early Use of the NMDA Receptor Antagonist Ketamine in Refractory and Superrefractory Status Epilepticus.
Zeiler FA. Zeiler FA. Crit Care Res Pract. 2015;2015:831260. doi: 10.1155/2015/831260. Epub 2015 Jan 12. Crit Care Res Pract. 2015. PMID: 25649724 Free PMC article. Review. - Defining "epileptogenesis" and identifying "antiepileptogenic targets" in animal models of acquired temporal lobe epilepsy is not as simple as it might seem.
Sloviter RS, Bumanglag AV. Sloviter RS, et al. Neuropharmacology. 2013 Jun;69:3-15. doi: 10.1016/j.neuropharm.2012.01.022. Epub 2012 Feb 4. Neuropharmacology. 2013. PMID: 22342985 Free PMC article. Review. - Selective neurotoxic lesions of basolateral and central nuclei of the amygdala produce differential effects on fear conditioning.
Koo JW, Han JS, Kim JJ. Koo JW, et al. J Neurosci. 2004 Sep 1;24(35):7654-62. doi: 10.1523/JNEUROSCI.1644-04.2004. J Neurosci. 2004. PMID: 15342732 Free PMC article. - Neuroprotection by glutamate receptor antagonists against seizure-induced excitotoxic cell death in the aging brain.
Schauwecker PE. Schauwecker PE. Exp Neurol. 2010 Jul;224(1):207-18. doi: 10.1016/j.expneurol.2010.03.013. Epub 2010 Mar 29. Exp Neurol. 2010. PMID: 20353782 Free PMC article.