preproenkephalin and Epilepsy--Temporal-Lobe

Previous studies have reported the association of prodynorphin (PDYN) promoter polymorphism with temporal lobe epilepsy (TLE) susceptibility, but the results remain inconclusive. To further precisely evaluate this association, we performed a meta-analysis. Published studies of TLE and PDYN polymorphism up to February 2015 were identified. Subgroup analysis by TLE subtype was performed. Moreover, sensitivity, heterogeneity, and publication bias were also analyzed. Seven case-control studies were finally included in this meta-analysis with 875 TLE cases and 1426 controls. We did not find synthetic evidence of association between PDYN promoter polymorphism and TLE susceptibility (OR=1.184, 95% CI: 0.873-1.606, P=0.277). Similar results were also obtained in non-familial-risk TLE subgroup. However, in the familial-risk TLE subgroup analysis, a significant association was observed (OR=1.739, 95% CI: 1.154-2.619, P=0.008). In summary, this meta-analysis suggests that PDYN gene promoter polymorphism might contribute to familial-risk TLE.

Topics: Case-Control Studies; Enkephalins; Epilepsy, Temporal Lobe; Family; Gene Expression; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Inheritance Patterns; Odds Ratio; Polymorphism, Genetic; Prognosis; Promoter Regions, Genetic; Protein Precursors

We performed an association study in a population of patients with Mesial Temporal Lobe Epilepsy (TLE) with Hippocampal Sclerosis (MTEHS) together with a systematic revision of the literature to investigate the role of transcriptionally less active polymorphic alleles of Prodynorphin (PDYN) gene in this pathology. We included 102 patients with a diagnosis of MTEHS and 86 healthy controls. The positive antecedent of family history for epileptic events defined a TLE subgroup with familial predisposition for epileptic disorders. The PDYN promoter polymorphism was genotyped by means of a PCR assay. For meta-analysis, we identified case-control association studies between TLE and PDYN by searching PUBMED. The pooled OR was estimated using a fixed effects model under dominant and co-dominant heredity models. No differences in genotypic and allelic frequencies were found between cases and controls (p=0.61) in our population, neither in the whole cohort nor in the analysis limited to TLE with familial predisposition (p=0.71). The Meta-Analysis included 591 TLE patients and 1117 healthy controls. We found an association between L allele (p=0.003; OR=1.40; IC 95=1.12-1.74) and a modestly higher risk to develop TLE in the group of patients with familial predisposition. Therefore, functional allelic variants in the PDYN promoter might modify the risk to develop TLE in subjects with familial predisposition.

Topics: Alleles; Biomarkers; Case-Control Studies; Enkephalins; Epilepsy, Temporal Lobe; Humans; Promoter Regions, Genetic; Protein Precursors; Transcription, Genetic

Dynorphin neuropeptides are believed to act as endogenous anticonvulsants, though direct evidence for such a role in humans is sparse. We now report pronounced increases of prodynorphin mRNA expression in the dentate gyrus of patients with temporal lobe epilepsy in comparison to controls. We detected a conspicuously right skewed, bimodal distribution of mRNA levels among patients, suggestive of a dynamic up-regulation of prodynorphin expression in epilepsy. Highest transcript levels were seen postictally. Our data argue for an essential role of dynorphin in the termination of seizures.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Carbon Isotopes; Child; Child, Preschool; Dentate Gyrus; Diprenorphine; Enkephalins; Epilepsy, Temporal Lobe; Female; Genotype; Humans; Male; Middle Aged; Polymorphism, Genetic; Postmortem Changes; Protein Precursors; RNA, Messenger; Up-Regulation; Young Adult

The objective of this study is to replicate previously published results regarding the involvement of several susceptibility genes in temporal lobe epilepsy (TLE): interleukin 1beta (IL-1beta), interleukin 1beta (IL-1alpha), interleukin 1RA (IL-1RA), apolipoprotein E (ApoE) and prodynorphin (PDYN). We used a case-control approach comparing several polymorphisms within these candidate genes between unrelated TLE patients and matched controls. We were thus able to confirm the role of ApoE, IL-1alpha and IL-1RA genes in TLE disease, but failed to confirm the involvement of IL-1beta and PDYN. This failure should be interpreted with caution, as this may be due to the small size of our study groups and the resultant lack of statistical power.

Topics: Adolescent; Adult; Apolipoproteins E; Case-Control Studies; Child; Cohort Studies; DNA Mutational Analysis; Enkephalins; Epilepsy, Temporal Lobe; Gene Frequency; Genetic Markers; Genetic Predisposition to Disease; Genetic Testing; Genotype; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1alpha; Interleukin-1beta; Interleukins; Polymorphism, Genetic; Protein Precursors

Autosomal dominant lateral temporal epilepsy (ADTLE) is a genetically transmitted epileptic syndrome characterized by focal seizures with predominant auditory symptoms likely originating from the lateral region of the temporal lobe. Mutations in coding region or exon splice sites of the leucine-rich, glioma-inactivated 1 (LGI1) gene account for about 50% of ADLTE families. De novo LGI1 mutations of the same kind have also been found in about 2.5% of non-familial cases with idiopathic partial epilepsy with auditory features (IPEAF). In both conditions, mutations in the LGI1 promoter region have not been reported. We sequenced the minimal promoter region of LGI1 in the probands of 16 ADLTE families and in 104 sporadic IPEAF patients and no mutations clearly linked to the disease were found. However, two polymorphisms, -500G>A and -507G>A, with potential functional implications were identified and analysed in the cohort of sporadic IPEAF patients but their frequencies did not differ from those found in a control population of similar age, gender and geographic origin. We also analysed in our study population the GABA(B) receptor 1 c.1465G>A and the prodynorphin promoter 68-bp repeat polymorphisms, previously associated with temporal lobe epilepsy. None of these polymorphisms showed a significant association with IPEAF, whereas a tendency towards association with the prodynorphin low expression (L) alleles was found in the small group of ADLTE index cases, in agreement with previous studies suggesting that this polymorphism is a susceptibility factor in familial forms of temporal lobe epilepsy.

Topics: Base Sequence; Enkephalins; Epilepsy, Temporal Lobe; Genetic Predisposition to Disease; Humans; Intracellular Signaling Peptides and Proteins; Mutation; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Protein Precursors; Proteins; Receptors, GABA-B

Neuropsychiatric disorders are one of the main challenges of human medicine with epilepsy being one of the most common serious disorders of the brain. Increasing evidence suggest neuropeptides, particularly the opioids, play an important role in epilepsy. However, little is known about the mechanisms of the endogenous opioid system in epileptogenesis and epilepsy. Therefore, we investigated the role of endogenous prodynorphin-derived peptides in epileptogenesis, acute seizure behaviour and epilepsy in prodynorphin-deficient mice. Compared with wild-type littermates, prodynorphin knockout mice displayed a significantly reduced seizure threshold as assessed by tail-vein infusion of the GABA(A) antagonist pentylenetetrazole. This phenotype could be entirely rescued by the kappa receptor-specific agonist U-50488, but not by the mu receptor-specific agonist DAMGO. The delta-specific agonist SNC80 decreased seizure threshold in both genotypes, wild-type and knockout. Pre-treatment with the kappa selective antagonist GNTI completely blocked the rescue effect of U-50488. Consistent with the reduced seizure threshold, prodynorphin knockout mice showed faster seizure onset and a prolonged time of seizure activity after intracisternal injection of kainic acid. Three weeks after local injection of kainic acid into the stratum radiatum CA1 of the dorsal hippocampus, prodynorphin knockout mice displayed an increased extent of granule cell layer dispersion and neuronal loss along the rostrocaudal axis of the ipsi- and partially also of the contralateral hippocampus. In the classical pentylenetetrazole kindling model, dynorphin-deficient mice showed significantly faster kindling progression with six out of eight animals displaying clonic seizures, while none of the nine wild-types exceeded rating 3 (forelimb clonus). Taken together, our data strongly support a critical role for dynorphin in the regulation of hippocampal excitability, indicating an anticonvulsant role of kappa opioid receptors, thereby providing a potential target for antiepileptic drugs.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Benzamides; Cell Count; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Epilepsy, Temporal Lobe; Guanidines; Hippocampus; Kindling, Neurologic; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphinans; Naltrexone; Nerve Degeneration; Piperazines; Protein Precursors; Receptors, Opioid, kappa; Synaptic Transmission; Time Factors

Topics: Enkephalins; Epilepsy, Temporal Lobe; Humans; Polymorphism, Genetic; Promoter Regions, Genetic; Protein Precursors

Topics: Adult; Aged; Alleles; Confidence Intervals; Enkephalins; Epilepsy, Temporal Lobe; Female; Genotype; Humans; Male; Middle Aged; Odds Ratio; Polymorphism, Genetic; Promoter Regions, Genetic; Protein Precursors

The prodynorphin gene (PDYN) encoding the anticonvulsant peptide dynorphin is a strong candidate for a seizure suppressor gene and thus a possible modulator of susceptibility to temporal lobe epilepsy. We performed a case control association study in 155 patients with nonlesional temporal lobe epilepsy and 202 controls and found that PDYN promotor low-expression L-alleles confer an increased risk for temporal lobe epilepsy in patients with a family history for seizures. Irrespective of the familial background, L-homozygotes display a higher risk for secondarily generalized seizures and status epilepticus.

Topics: Enkephalins; Epilepsy, Temporal Lobe; Female; Genetic Predisposition to Disease; Humans; Male; Polymorphism, Genetic; Promoter Regions, Genetic; Protein Precursors; Risk Factors; Severity of Illness Index

Levels of mRNA for c-fos and prodynorphin were studied by in situ hybridization in adjacent coronal sections taken from kindled rats 30-60 min after the last seizure. Within this time frame, expression of both genes was induced in multiple brain areas. Anatomical colocalization of the induced gene expressions was found in the hippocampus. Induction of c-fos in the dentate gyrus was bilateral and symmetrical in a subgroup of rats, ipsilateral in another subgroup and absent in a third subgroup. However, no relative increase was observed in the ipsilateral compared with the contralateral prodynorphin expression in the dentate gyrus when c-fos expression was induced ipsilaterally only. These observations suggest that, at variance with other experimental situations, Fos is not involved in the mechanisms of kindled seizure-induced activation of prodynorphin transcription in the rat forebrain.

Topics: Animals; Brain; Disease Models, Animal; Electric Stimulation; Enkephalins; Epilepsy, Temporal Lobe; Gene Expression; In Situ Hybridization; Kindling, Neurologic; Male; Nerve Tissue Proteins; Protein Precursors; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; RNA, Messenger

Expression of the opioid peptides dynorphin and enkephalin is altered within the first 24 h after acutely induced seizures in certain experimental models of epilepsy. Using in situ hybridization, we examined the expression of prodynorphin and preproenkephalin messenger RNA acutely following induction of kindling with recurrent seizures and in two models of chronic temporal lobe epilepsy: (i) rats fully kindled with rapidly recurring hippocampal seizures; and (ii) rats surviving after self-sustaining limbic status epilepticus induced with focal electrical stimulation of the hippocampus. In naive animals, a ventral-dorsal gradient was identified in the expression of both prodynorphin and preproenkephalin messenger RNA in the dentate gyrus and expression of prodynorphin message was demonstrated for the first time in the ventral portion of cornu Ammonis regio superior. After stimulation producing rapidly recurring hippocampal seizures, acute decreases in prodynorphin messenger RNA were seen in the dentate gyrus and cornu Ammonis regio superior at 24 h after the last seizure. In contrast, increases in preproenkephalin messenger RNA expression were seen acutely in the dentate gyrus, with a decrease seen in the entorhinal cortex. The change in prodynorphin message expression in cornu Ammonis regio superior persisted in kindled animals that were studied after one month seizure-free period. There were no changes in preproenkephalin message in kindled animals studied after the one month seizure-free interval. No statistically significant changes were found for either prodynorphin or preproenkephalin message in the post-self-sustaining limbic status epilepticus group at one month following induced seizures. Acute changes in peptide expression may contribute to increased excitation in the dentate gyrus during induction of kindling, while the chronic change identified in cornu Ammonis regio superior may contribute directly to persistently increased excitability in this region.

Topics: Animals; Autoradiography; Basal Ganglia; Disease Models, Animal; Enkephalins; Epilepsy, Temporal Lobe; Gene Expression; Hippocampus; Male; Opioid Peptides; Protein Precursors; Rats; RNA, Messenger