Brainstem activity, apnea, and death during seizures induced by intrahippocampal kainic acid in anaesthetized rats (original) (raw)
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On the relation between seizures and brain lesions after intracerebroventricular kainic acid
Neuroscience Letters, 1988
To analyze the relation between kainic acid-induced limbic seizures and the associated brain lesions, various doses of kainic acid ( 117 940 pmol) were administered intracerebroventricularly to unanesthetized rats. Rats which experienced status epilepticus developed lesions in several limbic, neocortical and thalamic regions. However, rats which experienced only temporally discrete seizures (less than 30 min each) suffered neuronal degeneration exclusively in the CA3 CA4 area ipsilateral to the kainic acid infusion, even when other regions exhibited the same total electrographic seizure duration. These results can best be explained by postulating that, in addition to evoking seizures, kainic acid also enhances the toxic effects of seizures on CA3 CA4 neurons.
SUMMARY Purpose: Models of temporal lobe epilepsy are commonly utilized to study focal epileptogenesis and ictogenesis. The criteria that define animal models representative of human mesial temporal lobe may vary in different laboratories. We describe herein a focal epilepsy model of mesial temporal (hippocampal) origin that relies on the analysis of interictal and ictal electroencephalography (EEG) patterns and on their correlation with seizure symptoms and neuropathologic findings. The study is based on guinea pigs, a species seldom utilized to develop chronic epilepsy models. Methods: Young adult guinea pigs were bilaterally implanted under isoflurane anesthesia with epidural electrodes over somatosensory cortex and depth electrodes in CA1 hippocampal region. A stainless steel guide can-nula was positioned unilaterally in the right dorsal hippo-campus to inject 1 ll of 0.9% NaCl solution containing 1 lg kainic acid (KA). One week after surgery, continuous 24 h/day video-EEG monitoring was performed 48 h before and every other week after KA injection, for no <1 month. EEG data were recorded wide-band at 2 kHz. After video-EEG monitoring, brains were analyzed for thionine and Timm staining and glial fibrillary acid protein (GFAP) immunostaining. Key Findings: Unilateral injection of KA in dorsal hippo-campus of guinea pigs induces an acute nonconvulsive status epilepticus (SE) that terminates within 24 h (n = 22). Chronic seizures with very mild motor signs (undetectable without EEG monitoring) and highly variable recurrence patterns appear in 45.5% (10 of 22) KA-treated animals, with variable delays from the initial SE. In these animals interictal events, CA1 cell loss, gliosis, and altered Timm staining pattern were observed. The induction of a chronic condition did not correlate with the duration of the nonconvulsive acute SE, but correlated with the extension and quality of neuropathologic damage. Significance: We demonstrate that a model of hippocam-pal (mesial temporal lobe) epilepsy can be developed in the guinea pig by intrahippocampal injection of KA. Seizure events in this model show little behavioral signs and may be overlooked without extensive video-EEG monitoring. The establishment of a chronic epileptic condition correlates with the extension of the hippocampal damage (mainly cell loss and gliosis) and not with the intensity of the initial SE. KEY WORDS: Guinea pig, Intrahippocampal kainic acid injection, Mesial temporal lobe epilepsy model.
Kainic acid neurotoxicity and seizures
Neuropharmacology, 1981
The effects of anesthetics and anticonvulsants on the neurotoxic effects of kainic acid (2.3 nmol) injected into the rat hippocampus and striatum have been examined with regard to neurochemical, histological and electroencephalographic alterations. Brief anesthesia with ether resulted in seizures and severe degeneration of the hippocampal CA,_, pyramids and granule cells. Prolonged anesthesia (> 300 min) with chloral hydrate-pentobarbital or with y-butyrolactone protected most hippocampal neurons and blocked seizures. Phenobarbital (100 mg/kg) prevented cortical seizures but provided minimal protection against hippocampal neuronal degeneration. Prolonged anesthesia (> 300 min) with chloral hydrate-pentobarbital also attenuated the neurotoxic effects of kainic acid in the striatum. The anesthetic and not the anticonvulsant action of drugs accounted for the protection against the neurotoxicity of kainic acid at the site of injection.
THE ROLE OF EPILEPTIC ACTIVITY IN HIPPOCAMPAL AND 'REMOTE' CEREBRAL LESIONS INDUCED BY KAINIC ACID
Kainic acid (KA) was injected systemically, intracerebroventricularly (i.c.v.) and focally in the amygdala and other deep brain structures in the rat. EEG and behavioral changes were studied in relation to the neuropathology which developed subsequently. Following intra-amygdaloid KA injection, diazepam blocked the epileptic events induced by the toxin, and abolished the neuronal loss usually seen in the lateral septum, claustrum, and contralateral cortex and hippocampus. The lesions in medial thalamic structures and ipsilateral hippocampus were also reduced by diazepam. Prior transection of the perforant path ipsilateral to the KA injection also decreased the severity of the electrographic and motor effects of the toxin and similarly reduced the extent of distant ('remote') pathological brain damage. Neither diazepam nor perforant path transection reduced the damage at the site of KA injection. Kainic acid (0.4-2/~g) injected into the bed nucleus of the stria terminalis (BST) or the medial septum produced seizures with a longer latency and little brain damage outside the injection site. In contrast, intrastriatal KA injections were followed by ipsilateral hippocampal lesions. i.c.v. Injection of KA (0.4-1.6/zg) produced a complex syndrome which included bilateral exophthalmos, mydriasis, foaming, tremor of the vibrissae, and paw and body tremor. The pattern of brain damage resembled that seen following intraamygdaloid administration of the toxin. In addition, however, there was a bilateral necrosis of the pyriform and prepyriform cortices up to the rhinal fissure. Systemic administration of diazepam (i.p.) reduced the extent of the damage and in particular completely prevented the cortical damage.
Kainic acid as a tool for the study of temporal lobe epilepsy
Life Sciences, 1981
Temporal lobe epllepsy (llmblc epilepsy, complex partial epllepsy, psychomotor epilepsy) ms the most devastatlng form of epilepsy commonly encountered in the adult populatlon. The attacks involve loss of consciousness, thus limiting performance of normal functlons and exposing the individual to bodily injury. Moreover, long-standlng or pharmacologically intractable temporal lobe epilepsy is frequently assoclated wlth the loss of-neurons from the h]ppocampus and other braln regions (Ammon's horn sclerosls (AHS)). Unfortunately, pharmacologlcally intractable cases are rather common, owing to the relatively low efficacy against thls condltion of the available anticonvulsants.
Brain Research, 1980
Intrastriatal injectmns of kainic acid m rats acutely induced repeated episodes of clonic convulsions. Spontaneously recurrent generahzed seizures and a potentlanon of the convulsant effects of pentylenetetrazol were then observed in most of the m lected rats several weeks after surgery. In additmn to marked loss of strmtal neurons, llmbic pathological alterations similar to those found in human temporal lobe epilepsy were observed in the brains of the kainic-acid treated rats. It is proposed that this preparation might serve as an animal model of human temporal lobe epilepsy.
The maturation of the seizure/brain damage syndrome produced by parenteral administration of kainate was studied in the rat. The motor, electrographic and metabolic alterations are described in the present report, the maturation of the pathological abnormalities and of the specific kainate binding sites are described in the two following companion papers. Parenteral kainate produces tonico-clonic seizures until the end of the third week of age when limbic motor signs (wet-dog shakes, facial myoclonia, paw tremor etc.) were first produced. Using the 2-deoxyglucose autoradiographic method, we found that in animals of 3 days of age and until the third week of age, kainate produced a rise in metabolism restricted to the hippocampus and lateral septum. This was paralleled by paroxysmal discharges which were recorded in the hippocampus. Starting from the end of the third week of age approximately-i.e. when the toxin produced limbic motor seizures-there was a rise of labelling in other structures which are part of or closely associated to the limbic system i.e. the amygdaloid complex, the mediodorsal and adjacent thalamic nuclei, piriform. entorhinal and rostra1 limbic cortices and areas of projection of the fornix. These metabolic maps are thus similar to those seen in adults. Two main conclusions can be drawn from these experiments: (1) kainate activates the hippocampus from a very early age probably by means of specific receptors present in this structure and (2) the limbic syndrome will only be produced by the toxin once the limbic circuitry-including in particular the amygdaloid complex-is activated by the procedure i.e. after the third week of age.