Benchmarking the proteomic profile of animal models of mesial temporal epilepsy

Abstract

Objectives We compared the proteomic signatures of the hippocampal lesion induced in three different animal models of mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE+HS): the systemic pilocarpine model (PILO), the intracerebroventricular kainic acid model (KA), and the perforant pathway stimulation model (PPS). Methods We used shotgun proteomics to analyze the proteomes and find enriched biological pathways of the dorsal and ventral dentate gyrus (DG) isolated from the hippocampi of the three animal models. We also compared the proteomes obtained in the animal models to that from the DG of patients with pharmacoresistant MTLE+HS. Results We found that each animal model presents specific profiles of proteomic changes. The PILO model showed responses predominantly related to neuronal excitatory imbalance. The KA model revealed alterations mainly in synaptic activity. The PPS model displayed abnormalities in metabolism and oxidative stress. We also identified common biological pathways enriched in all three models, such as inflammation and immune response, which were also observed in tissue from patients. However, none of the models could recapitulate the profile of molecular changes observed in tissue from patients. Significance Our results indicate that each model has its own set of biological responses leading to epilepsy. Thus, it seems that only using a combination of the three models may one replicate more closely the mechanisms underlying MTLE+HS as seen in patients.

Gene expression profile suggests different mechanisms underlying sporadic and familial mesial temporal lobe epilepsy

“…These changes suggest that proteostatic stress may be occurring, leading to inappropriate protein translation, transcription, folding, localization, and degradation. 82,83 Interestingly, regulation of mRNA processing and protein translation are directly linked to cellular energy metabolism, 84–86 which has been associated with epilepsy, 87,88 and is also observed as one of the mechanisms linked to abnormally regulated genes in tissue from familial MTLE in the present study (Figures 4 to 6). However, there was a more prominent enrichment of biological pathways linked to the regulation of energy metabolism in samples from patients with sporadic MTLE, making it the mechanism predominantly involved in sporadic MTLE in the present study.…”

PET Imaging and Neurohistochemistry Reveal that Curcumin Attenuates Brain Hypometabolism and Hippocampal Damage Induced by Status Epilepticus in Rats

“…Even though Cremophor EL is a non-inert relatively nontoxic solvent, it is important to mention that several reports suggest that it can induce serious complications such as anaphylactoid-hypersensitivity and cellular toxicity, especially when administered intravenously [36]. Nevertheless, observational follow-up of our rats, including BW changes, As previously mentioned, the SE induced by lithium-pilocarpine is an animal model of epileptogenesis that resembles many, but not all, pathological features of human TLE [15][16][17]. In so far, to date few studies have tackled the therapeutic efficacy of curcumin (administrated either as a single dose or repeatedly) on the pilocarpine model of SE in rats [24,25,27,28,37].…”

“…Epileptogenesis is associated, among others, with neurochemical imbalances, neurodegeneration, neuroinflammation, and reactive gliosis, as well as synapsis modification and reorganization of specific brain areas [19,38]. Many of these alterations are present in the rodent pilocarpine and lithium-pilocarpine SE models [6,16,17]. In these models, pilocarpine administration results in a SE that is followed by a silent latency period during which generalized glucose hypometabolism occurs concomitantly with severe neurodegeneration and neuronal death, neuroinflammation, and intense reactive gliosis, affecting both astroglia and microglia [18][19][20], and ultimately leading to a chronic epileptic state characterized by spontaneous recurrent seizures.…”

“…As previously mentioned, the SE induced by lithium-pilocarpine is an animal model of epileptogenesis that resembles many, but not all, pathological features of human TLE, [15][16][17]. In so far, to date few studies have tackled the therapeutic efficacy of curcumin (administrated either as a single dose or repeatedly) on the pilocarpine model of SE in rats [24,25,27,28,37].…”

“…Pilocarpine, an alkaloid obtained from the leaves of different species from genus Pilocarpus , is often administered intraperitoneally to trigger status epilepticus (SE), resulting in an animal model of epileptogenesis that resembles many, but not all the behavioral, electrographic, proteomic, and neuropathological features in human TLE 15 , 16 , 17 , being a suitable tool to study the potential antiseizure, antiepileptic and neuroprotective drugs.…”