Abstract
ObjectiveIn order to better investigate the cause/effect relationships of human mesial temporal lobe epilepsy (mTLE), we hereby describe a new non-human primate model of mTLE.MethodsTen macaques were studied and divided into 2 groups: saline control group (n = 4) and kainic acid (KA) injection group (n = 6). All macaques were implanted bilaterally with subdural electrodes over temporal cortex and depth electrodes in CA3 hippocampal region. KA was stereotaxically injected into the right hippocampus of macaques. All animals were monitored by video and electrocorticography (ECoG) to assess status epilepticus (SE) and subsequent spontaneous recurrent seizures (SRS). Additionally, in order to evaluate brain injury produced by SE or SRS, we used both neuroimaging, including magnetic resonance image (MRI) & magnetic resonance spectroscopy (MRS), and histological pathology, including Nissl stainning and glial fibrillary acid protein (GFAP) immunostaining.ResultsThe typical seizures were observed in the KA-injected animal model. Hippocampal sclerosis could be found by MRI & MRS. Hematoxylin and eosin (H&E) staining and GFAP immunostaining showed neuronal loss, proliferation of glial cells, formation of glial scars, and hippocampal atrophy. Electron microscopic analysis of hippocampal tissues revealed neuronal pyknosis, partial ribosome depolymerization, an abnormal reduction in rough endoplasmic reticulum size, expansion of Golgi vesicles and swollen star-shaped cells. Furthermore, we reported that KA was able to induce SE followed by SRS after a variable period of time. Similar to human mTLE, brain damage is confined to the hippocampus. Accordingly, hippocampal volume is in positive correlations with the neuronal cells count in the CA3, especially the ratio of neuron/glial cell.ConclusionsThe results suggest that a model of mTLE can be developed in macaques by intra-hippocampal injection of KA. Brain damage is confined to the hippocampus which is similar to the human mTLE. The hippocampal volume correlates with the extension of the hippocampal damage.
Highlights
Mesial temporal lobe epilepsy with hippocampal sclerosis is one of the most common forms of drug-resistant partial epilepsy in humans [1]
In 6 macaques with kainic acid (KA) injection, initially, ictal EEG event was observed in the treated hippocampus; ictal activity could propagate from the onset site to other recording electrodes
The most frequent seizure pattern observed during the initial phase of the acute status epilepticus (SE) (n = 6) was characterized by low amplitude, high frequency spikes (16–18 Hz, 100–200 uV) at seizure onset, followed by dissemination of high amplitude, high frequency spikes(16–18 Hz, 300–500 uV) that subsequently organized in burst of high amplitude, and high frequency spikes(16–18 Hz, 300–500 uV) (Fig. 2)
Summary
Mesial temporal lobe epilepsy (mTLE) with hippocampal sclerosis is one of the most common forms of drug-resistant partial epilepsy in humans [1]. Spontaneous seizures in mTLE are believed to be preceded by a precipitating event, such as brain trauma, cerebral infection, status epilepticus (SE), genetic factors or anoxic brain episodes These early injuries may trigger neurobiological changes that result in a chronic epileptic condition clinically characterized by partial seizures with occasional secondary generalization [2]. Intraperitoneal injection of proconsulsive drugs, such as pilocarpine and kainic acid (KA), is the most widely used procedure to induce mTLE in rodents [7,8,9,10] These systematic drug-induced models have been criticized recently, because they present with features that are not typical of human mTLE, such as bilateral hippocampal alterations, extensive damage in brain regions exceeding the temporal lobe, and the occurrence of generalized tonic-clonic seizures [4]. Unlike systemic pilocarpine and KA models, structural alterations are mainly ipsilateral to the injected dorsal hippocampus in local intrahippocampal KA models
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