dynorphins and Sclerosis

This review addresses the main neuropathologic advances that have been made over recent years in the study of focal lesions in patients with epilepsy undergoing surgical treatment. There have been revisions and simplifications to the classification of focal cortical dysplasias. Hippocampal sclerosis is a well-characterized lesion but further pathologic studies have explored its possible relationship to temporal lobe developmental lesions, ongoing neurogenesis and mechanisms of its epileptogenicity. The important contribution of astrocytes to epileptogenesis is also unfolding and is briefly discussed, as are the possible cellular mechanisms of drug resistance.

Topics: Brain Neoplasms; Cytokines; Dynorphins; Epilepsy; Hippocampus; Humans; Immunohistochemistry; Nervous System Diseases; Neural Cell Adhesion Molecules; Sclerosis

Hippocampal sclerosis (HS) is the most common surgical pathology associated with mesial temporal lobe epilepsy (MTLE). HS is typically characterized by mossy fiber sprouting (MFS) and reorganization of neuropeptide Y (NPY) fiber networks in the dentate gyrus. One potential cause of postoperative seizure recurrence following temporal lobe surgery may be the presence of seizure-associated bilateral hippocampal damage. We aimed to investigate patterns of hippocampal abnormalities in a postmortem series as identified by NPY and dynorphin immunohistochemistry.. Analysis of dentate gyrus fiber reorganization, using dynorphin (to demonstrate MFS) and NPY immunohistochemistry, was carried out in a postmortem epilepsy series of 25 cases (age range 21-96 years). In 9 patients, previously refractory seizures had become well controlled for up to 34 years prior to death.. Bilateral MFS or abnormal NPY patterns were seen in 15 patients including those with bilateral symmetric, asymmetric, and unilateral HS by conventional histologic criteria. MFS and NPY reorganization was present in all classical HS cases, more variably in atypical HS, present in both MTLE and non-MTLE syndromes and with seizure histories of up to 92 years, despite seizure remission in some patients.. Synaptic reorganization in the dentate gyrus may be a bilateral, persistent process in epilepsy. It is unlikely to be sufficient to generate seizures and more likely to represent a seizure-induced phenomenon.

Topics: Adult; Aged; Aged, 80 and over; Cell Count; Dentate Gyrus; Dynorphins; Epilepsy, Temporal Lobe; Functional Laterality; Humans; Immunohistochemistry; Middle Aged; Mossy Fibers, Hippocampal; Neuropeptide Y; Sclerosis; Young Adult

This study is a retrospective analysis of the pathology of the hippocampus from patients with medically intractable temporal lobe epilepsy. We attempted to relate neuronal density, immunohistochemistry, electrophysiologic data, and surgical outcome.. Immunostaining patterns for neuropeptide Y, somatostatin, substance P, and dynorphin defined the immunohistochemical characteristics of the hippocampi. Neuronal densities were determined by microscopic cell counts. Sharp electrode recordings from dentate granule cells determined measures of inhibition and excitation.. Patient hippocampi without evidence of sclerosis generally resembled autopsy controls on the basis of neuronal densities of hippocampal subfields and patterns of immunostaining. The nonsclerotic hippocampi were divisible into two subgroups on the basis of neuronal density correlations between hippocampal subfields, the excitability of dentate granule cells, etiology, and surgical outcome. Hippocampi with sclerosis were divisible into those with significant neuronal loss confined to area CA1 and those with neuronal loss throughout the hippocampus and dentate gyrus. In the former, the dentate gyrus resembled in morphology the nonsclerotic hippocampi but with slightly increased excitability of the dentate granule cells. The hippocampi with more extensive neuronal loss had changes in immunostaining patterns associated with the dentate gyrus, correlated with significant hyperexcitability of dentate granule cells. The surgical outcome, with the exception of one group, was good in approximately 70-90%.. Hippocampi from patients with intractable temporal lobe epilepsy can be assigned to several groups on the basis of pathophysiology. Different pathologies may represent differing causative mechanisms of intractable temporal lobe epilepsy and be predictive of surgical outcome.

Topics: Adult; Apoptosis; Cell Count; Culture Techniques; Dentate Gyrus; Dynorphins; Electroencephalography; Epilepsy, Temporal Lobe; Evoked Potentials; Female; Follow-Up Studies; Hippocampus; Humans; Immunoenzyme Techniques; Interneurons; Male; Neurons; Neuropeptide Y; Reference Values; Retrospective Studies; Sclerosis; Somatostatin; Substance P; Treatment Outcome

The endogenous kappa receptor selective opioid peptide dynorphin has been shown to inhibit glutamate receptor-mediated neurotransmission and voltage-dependent Ca2+ channels. It is thought that dynorphin can be released from hippocampal dentate granule cells in an activity-dependent manner. Since actions of dynorphin may be important in limiting excitability in human epilepsy, we have investigated its effects on voltage-dependent Ca2+ channels in dentate granule cells isolated from hippocampi removed during epilepsy surgery. One group of patients showed classical Ammon's horn sclerosis characterized by segmental neuronal cell loss and astrogliosis. Prominent dynorphin-immunoreactive axon terminals were present in the inner molecular layer of the dentate gyrus, indicating pronounced recurrent mossy fiber sprouting. A second group displayed lesions in the temporal lobe that did not involve the hippocampus proper. All except one of these specimens showed a normal pattern of dynorphin immunoreactivity confined to dentate granule cell somata and their mossy fiber terminals in the hilus and CA3 region. In patients without mossy fiber sprouting the application of the kappa receptor selective opioid agonist dynorphin A ([D-Arg6]1-13, 1 microM) caused a reversible and dose-dependent depression of voltage-dependent Ca2+ channels in most granule cells. These effects could be antagonized by the non-selective opioid antagonist naloxone (1 microM). In contrast, significantly less dentate granule cells displayed inhibition of Ca2+ channels by dynorphin A in patients with mossy fiber sprouting (Chi-square test, P < 0.0005). The lack of dynorphin A effects in patients showing mossy fiber sprouting compares well to the loss of kappa receptors on granule cells in Ammon's horn sclerosis but not lesion-associated epilepsy. Our data suggest that a protective mechanism exerted by dynorphin release and activation of kappa receptors may be lost in hippocampi with recurrent mossy fiber sprouting.

Topics: Adolescent; Adult; Age of Onset; Axons; Calcium Channels, N-Type; Child; Dentate Gyrus; Dynorphins; Electric Stimulation; Epilepsy, Temporal Lobe; Female; Hippocampus; Humans; In Vitro Techniques; Male; Middle Aged; Naloxone; Nerve Endings; Nerve Fibers; Neurons; Patch-Clamp Techniques; Pyramidal Cells; Sclerosis