Effects Of Peripheral Benzodiazepine Receptors On Brain Aging And Seizure Susceptibility

Objective1. Selective decreases of peripheral-type benzodiazepine receptors (PBRs) were noticed in some brain regions in normal aging rats. Whether the changes of PBRs during aging affect the intellectual status of aged animals remains unclear. In order to explore the role of PBRs in aging, changes of PBRs in subcellular fractions in the brain cells from aged rats and the recuperative effects of dehydroepiandrosterone (DHEA) were investigated.2. PBRs seem to be involved in the pathogenesis of epileptic seizures and may affect seizure susceptibility. In order to explore the role of PBRs in seizure susceptibility, changes of PBRs in platelet membrane from epilepsy patients, seizure behaviors and PBRs levels in different brain areas in epilepsy rats and anticonvulsant actions of topiramate (TPM) were investigated.Methods1. Changes of PBRs in subcellular fractions of brain cells and in platelet membrane during ageing and recuperative effects of DHEA(1) Sprague-Dawley (SD) rats of both sexes were divided into birth, 3-, 12-and 24-month groups. After decapitation, the membrane of platelets, mitochondria of cerebral cortex and cerebellum, synaptosomes of hippocampus and membrane from pituitary gland cells were purified. PBRs binding was examined by radioligand assay.(2) SD rats were randomly assigned to five groups as follows: saline control group, D-galactose group, DHEA-treated normal group, vehicle control group and DHEA-treated senescent group. All mimetic aging rats were induced by D-galactose (s.c). Meanwhile, DHEA-treated rats received DHEA (i.p.) every other day for 28 days. Spatial learning and memory were assessed by Morriswater maze test. Following behavioral testing, all rats were decapitated and cerebral cortex and hippocampus were removed immediately. Then, mitochondria and synaptosomes were purified respectively. PBRs binding parameters, maximal binding site density (B_max) and equilibrium dissociation constant (Kd), were estimated after [³H]PK11195 binding assays.2. Effects of PBRs on seizure susceptibility and anticonvulsant efficacy of TPM(1) Thirty-seven patients with intractable epilepsy and fifty healthy volunteers participated in this trial. The membrane of platelets from venous blood was prepared. PBRs binding was examined.(2) Seven days after kainic acid (KA) (8mg·kg^-1) injection, seizure susceptibility was detected with KA (4mgkg^-1, s.c.) in male SD rats. The KA-induced seizure rats were divided into susceptible group and nonsusceptible group according to whether the seizure susceptibility developed in rats. In addition, there were subconvulsive dose alone group and saline control group. After decapitation, mitochondria from cerebral cortex and synaptosomes from hippocampus were purified. PBRs binding assay was performed.(3) Male rats were randomly divided into control group, KA-induced seizure group, 10mg TPM group and 30mg TPM group. After three weeks of KA (10mg·kg^-1) injection, the effects of TPM were tested at two doses (10mg, 30 mg·kg^-1, s.c.) once a day for one week. After four weeks of KA injection, KA (5mg·kg^-1, s.c.) was injected in rats and seizure behaviors were investigated. Then, all rats were decapitated and hippocampus synaptosomes were purified. PBRs binding assay was performed.Results1. An age-related decrease was found for the specific binding of PBRs to cerebral cortex mitochondria, hippocampus synaptosomes, pituitary gland cells and platelets. PBRs binding in platelets was significantly related to those in cerebral cortex mitochondria, hippocampus synaptosomes as well as pituitary...