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1.
Neurosci Res ; 96: 45-53, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25697393

ABSTRACT

The use of NR2B antagonists in Parkinsonism is still controversial. To examine their anti-parkinsonian effects, the NR2B antagonist, ifenprodil, and L-DOPA were administered together and separately in hemiparkinsonian rats (hemi-PD) that were subjected to a cylinder test. Recovery from hypoactivity was achieved by single administration of 3-7 mg/kg of L-DOPA; however, improvement in the deficit of bilateral forelimb use was not observed. When administered alone, ifenprodil had no anti-parkinsonian effects; however, combined administration of ifenprodil and 7 mg/kg of L-DOPA significantly reversed the deficit of bilateral forelimb use without adversely affecting the L-DOPA-induced improvement in motor activity. Next, in order to identify the brain area influenced by L-DOPA and ifenprodil, quantitative analysis of L-DOPA-induced c-Fos immunoreactivity was performed in various brain areas of hemi-PD following administration of L-dopa with and without ifenprodil. Among brain areas with robust c-Fos expression within the motor loop circuit in dopamine-depleted hemispheres, co-administered ifenprodil markedly attenuated L-DOPA-induced c-Fos expression in only the subthalamic nucleus (STN), suggesting that the STN is the primary target for the anti-parkinsonian action of NR2B antagonists.


Subject(s)
Antiparkinson Agents/administration & dosage , Levodopa/administration & dosage , Parkinsonian Disorders/prevention & control , Piperidines/administration & dosage , Animals , Brain/drug effects , Brain/metabolism , Forelimb , Male , Motor Activity/drug effects , Parkinsonian Disorders/chemically induced , Proto-Oncogene Proteins c-fos/metabolism , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Subthalamic Nucleus/drug effects , Subthalamic Nucleus/metabolism
2.
Neurosci Res ; 80: 32-7, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24440197

ABSTRACT

Paclitaxel, one of the chemotherapeutic agents clinically used to treat several types of cancer, produces side effects such as peripheral neuropathy, sensory abnormalities, and hyperalgesia. Since hyperalgesia remains after cessation of paclitaxel therapy and becomes chronic, we hypothesize that alteration in memory and the cognitive process of pain underlies hyperalgesia. To test this hypothesis, we examined whether drug-induced hyperalgesia alters the affective component of pain and the NMDA-NR1 and mGluR1 receptors as a mediator for signal transmission and memory of pain. Mechanical sensitivity was measured by von Frey filament test after intraperitoneal injection of paclitaxel in rats. Paclitaxel-induced hyperalgesia was confirmed over almost the entire 14-day period of observation after the treatment. The effect of paclitaxel-induced hyperalgesia on the affective component of pain was assessed using pain-induced place aversion. The formalin-induced conditioned place aversion was completely abolished in the paclitaxel-treated rats. Immunoblot analysis of NR1 and mGluR1 protein levels in various brain regions was performed after paclitaxel treatment. Treatment reduced only the NR1 expression within the frontal cortex. These results suggest that the hypofunction of memory processes with the reduced NMDA receptors in the frontal cortex might be involved in the expression of abnormal emotional behaviors accompanied by hyperalgesia.


Subject(s)
Antineoplastic Agents, Phytogenic/toxicity , Frontal Lobe/drug effects , Hyperalgesia/chemically induced , Hyperalgesia/pathology , Paclitaxel/toxicity , Receptors, N-Methyl-D-Aspartate/metabolism , Analysis of Variance , Animals , Conditioning, Operant/drug effects , Formaldehyde/adverse effects , Frontal Lobe/metabolism , Hot Temperature/adverse effects , Male , Nociception/drug effects , Nociception/physiology , Pain Measurement , Pain Threshold/drug effects , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/genetics
3.
Brain Res ; 1306: 159-67, 2010 Jan 08.
Article in English | MEDLINE | ID: mdl-19766606

ABSTRACT

To test the hypothesis that the cellular mechanism whereby chronic deep brain stimulation of the subthalamic nucleus (STN-DBS) induces the improvement of motor deficits lasting after stimulation in the hemiparkinsonian (hemi-PD) rat involves the NMDA receptor-dependent processes in neurons receiving afferents from the STN, we examined whether the NMDA receptor antagonist prevents the alleviating after-effect of repeated STN-DBS on motor deficits in hemi-PD. The cylinder test was performed before and after repeated STN-DBS over 3 days in hemi-PD that received a unilateral injection of 6-OHDA into the medial forebrain bundle 3 weeks prior to STN-DBS experiments. No significant improvement in the reduced frequency of forelimb use and forelimb-use asymmetry was seen in the cylinder test after the single STN-DBS, while, when the STN-DBS was applied three times at intervals of 24 h, the improvement became apparent and significant only in the reduced frequency of forelimb use (akinesia) after termination of the stimulation, suggesting the alleviating after-effect of chronic stimulation. Then, the effects of intraperitoneal administration of the non-competitive NMDA receptor antagonist MK-801 and the competitive NMDA receptor antagonist CPP on the alleviating after-effect of the STN-DBS were examined in cylinder tests performed before and after repeated STN-DBS for 3 days in hemi-PD. Both MK-801 (0.1 mg/kg) and CPP (0.5 mg/kg) completely prevented the improvement of the akinetic motor deficit after repeated STN-DBS. These results support the hypothesis that activation of the NMDA receptor and subsequent cellular processes in neurons receiving the afferents from the STN may involve in the mechanism underlying the alleviating after-effect of chronic STN-DBS on the akinetic motor deficit in hemi-PD.


Subject(s)
Deep Brain Stimulation , Dyskinesias/therapy , Parkinsonian Disorders/therapy , Receptors, N-Methyl-D-Aspartate/metabolism , Subthalamic Nucleus/physiopathology , Animals , Dizocilpine Maleate/pharmacology , Dyskinesias/physiopathology , Excitatory Amino Acid Antagonists/pharmacology , Forelimb , Male , Motor Activity/drug effects , Motor Activity/physiology , Neuropsychological Tests , Oxidopamine , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/physiopathology , Piperazines/pharmacology , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Subthalamic Nucleus/drug effects , Time Factors
4.
Hum Gene Ther ; 19(4): 384-90, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18439125

ABSTRACT

There are a number of genetic diseases that affect the cochlea early in life, which require normal gene transfer in the early developmental stage to prevent deafness. The delivery of adenovirus (AdV) and adeno-associated virus (AAV) was investigated to elucidate the efficiency and cellular specificity of transgene expression in the neonatal mouse cochlea. The extent of AdV transfection is comparable to that obtained with adult mice. AAV-directed gene transfer after injection into the scala media through a cochleostomy showed transgene expression in the supporting cells, inner hair cells (IHCs), and lateral wall with resulting hearing loss. On the other hand, gene expression was observed in Deiters cells, IHCs, and lateral wall without hearing loss after the application of AAV into the scala tympani through the round window. These findings indicate that injection of AAV into the scala tympani of the neonatal mouse cochlea therefore has the potential to efficiently and noninvasively introduce transgenes to the cochlear supporting cells, and this modality is thus considered to be a promising strategy to prevent hereditary prelingual deafness.


Subject(s)
Cochlea/cytology , Cochlea/metabolism , Dependovirus/genetics , Genetic Vectors/genetics , Transduction, Genetic , Transgenes/genetics , Animals , Animals, Newborn , Cochlea/virology , Evoked Potentials, Auditory, Brain Stem , Female , Genetic Vectors/administration & dosage , Male , Mice , Mice, Inbred C57BL
5.
Brain Dev ; 30(5): 313-20, 2008 May.
Article in English | MEDLINE | ID: mdl-18358657

ABSTRACT

Synaptic release of the excitatory amino acid glutamate is considered as an important mechanism in the pathogenesis of ischemic brain damage in neonates. Synaptotagmin I is one of exocytosis-related proteins at nerve terminals and considered to accelerate the exocytosis of synaptic vesicles by promoting fusion between the vesicles and plasma membrane. To test the possibility that antisense in vivo knockdown of synaptotagmin I modulates the exocytotic release of glutamate, thus suppressing the excitotoxic intracellular processes leading to neuronal death following ischemia in the neonatal brain, we injected antisense oligodeoxynucleotides (ODNs) targeting synaptotagmin I (0.3 (AS), 0.15 (0.5 AS), or 0.03 microg (0.1 AS), or vehicle) into the lateral ventricles of 7-day-old rats by using a hemagglutinating virus of Japan (HVJ)-liposome mediated gene transfer technique. At 10 days of age, these rats were subjected to an electrical coagulation of the right external and internal carotid arteries, then the insertion of a solid nylon thread into the right common carotid artery toward the ascending aorta up to 10-12 mm from the upper edge of the sternocleidomastoid muscle. Cerebral ischemia was induced by clamping the left external and internal carotid arteries with a clip, and ended by removing the clip 2h later. Twenty-four hours after the end of ischemia, the extent of ischemic brain damage was neuropathologically and quantitatively evaluated in the neocortex and striatum. While the relative volume of damage in the cerebral cortex and striatum of the vehicle group was extended to 40% and 13.7%, respectively, that in the AS group was significantly reduced to 4.8% and 0.6%. In the 0.5 AS group, the relative volume of ischemic damage in the cerebral cortex and striatum was reduced to 20.5% and 15.4%, respectively, and the difference between the 0.5 AS group and vehicle group was statistically significant in the neocortex, but not in the striatum. These results indicated that antisense in vivo knockdown of synaptotagmin I successfully attenuated ischemic brain damage in neonatal rats and that the effect was dose-dependent. It was also suggested that this treatment was more effective in the neocortex than in the striatum in neonatal rats.


Subject(s)
Brain Injuries/therapy , Gene Transfer Techniques , Oligodeoxyribonucleotides, Antisense/therapeutic use , Sendai virus/physiology , Synaptotagmin I/metabolism , Animals , Animals, Newborn , Brain Injuries/pathology , Brain Ischemia/complications , Corpus Striatum/drug effects , Corpus Striatum/pathology , Corpus Striatum/virology , Dose-Response Relationship, Drug , Liposomes/therapeutic use , Neocortex/drug effects , Neocortex/pathology , Neocortex/virology , Rats , Rats, Wistar , Synaptotagmin I/genetics
6.
Brain Res ; 1095(1): 178-89, 2006 Jun 20.
Article in English | MEDLINE | ID: mdl-16729982

ABSTRACT

To produce an animal model of a dopa-responsive motor disorder with depletion of dopamine (DA) release in the striatum by dysfunction of the transmitter release machinery of the nigrostriatal DA system, we performed an intra-nigral injection of an HVJ-liposome gene transfer vector containing antisense oligodeoxynucleotides (ODNs) against synaptotagmin I (SytI), a key regulator of Ca(2+)-dependent exocytosis and endocytosis in adult rats. A unilateral intra-nigral injection of HVJ-liposome vectors containing antisense ODNs against SytI (syt-AS) caused a moderate disruption of methamphetamine-induced release of DA in the treated side of the striatum, while the syt-AS treatment did not affect physiological release of DA in the treated striatum. A bilateral intra-nigral injection of HVJ-liposome vectors containing syt-AS induced an impairment of the striatal DA-mediated acquisition of skilled behavior in a rotarod task without any deficits in general motor functions, such as spontaneous locomotor activity, motor adjusting steps, equilibrium function, or muscle strength. These findings suggest that an intra-nigral treatment with HVJ-liposome vectors containing syt-AS may cause a long-lasting nigral knockdown of SytI which, in turn, leads to a moderate dysfunction of the DA release machinery in the terminals of the nigrostriatal DA system and a subsequent mild depletion of DA release in the striatum.


Subject(s)
Corpus Striatum/metabolism , Gene Transfer Techniques , Motor Activity/physiology , Motor Skills Disorders/physiopathology , Oligonucleotides, Antisense/administration & dosage , Substantia Nigra/drug effects , Analysis of Variance , Animals , Behavior, Animal , Corpus Striatum/virology , Disease Models, Animal , Dopamine/metabolism , Immunohistochemistry/methods , Male , Methamphetamine/toxicity , Microdialysis/methods , Motor Activity/drug effects , Motor Skills/drug effects , Motor Skills/physiology , Motor Skills Disorders/etiology , Motor Skills Disorders/metabolism , Oligonucleotides, Antisense/genetics , Oxidopamine/toxicity , Rats , Rats, Wistar , Reaction Time/drug effects , Reaction Time/physiology , Rotarod Performance Test/methods , Substantia Nigra/injuries , Substantia Nigra/virology , Synaptotagmin I/deficiency
7.
Neurosci Res ; 51(3): 299-308, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15710494

ABSTRACT

In view of recent findings that suggest that the nigrostriatal dopamine (DA) system plays a role in motor control and the acquisition of habits and skills, we hypothesized that the striatum-based function underlying the acquisition of skilled behaviors might be more vulnerable to dopamine depletion than the motor control. To test this hypothesis, we investigated whether impaired acquisition of skilled behaviors occurs in a pre-symptomatic stage model of Parkinson's disease (PD). By using the microdialysis method and the 6-OHDA-technique to destroy dopamine neurons, we confirmed that rats with unilateral partial lesions of the nigral dopamine cells by 6-OHDA are suitable for a pre-symptomatic stage model of Parkinson's disease. The rats in this model exhibited moderate disruption of striatal dopamine release function and relatively intact motor functions. In a rotarod test, the impaired acquisition of skilled behavior occurred in rats with bilateral partial lesions of the nigral dopamine cells by 6-OHDA. These rats displayed intact general motor functions, such as locomotor activity, adjusting steps, equilibrium function and muscle strength. Based on these results, we concluded that the striatum-based function underlying the acquisition of skilled behaviors or sensorimotor learning may be more vulnerable to dopamine depletion than the motor control.


Subject(s)
Corpus Striatum/metabolism , Dopamine/deficiency , Motor Skills/physiology , Parkinson Disease/metabolism , Parkinson Disease/physiopathology , Amphetamine/pharmacology , Animals , Behavior, Animal , Cell Count/methods , Cell Survival/drug effects , Central Nervous System Stimulants/pharmacology , Corpus Striatum/drug effects , Disease Models, Animal , Exploratory Behavior/drug effects , Functional Laterality , Hindlimb Suspension/methods , Immunohistochemistry/methods , Male , Medial Forebrain Bundle/drug effects , Medial Forebrain Bundle/metabolism , Microdialysis/methods , Motor Activity/drug effects , Motor Activity/physiology , Oxidopamine/toxicity , Parkinson Disease/etiology , Rats , Rats, Wistar , Regression Analysis , Rotarod Performance Test/methods , Substantia Nigra/drug effects , Substantia Nigra/metabolism , Sympatholytics/toxicity , Time Factors , Tyrosine 3-Monooxygenase/metabolism
8.
Neurosci Res ; 49(2): 205-17, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15140563

ABSTRACT

Drebrin located in dendritic spines regulates their morphological changes and plays a role in the synaptic plasticity via spine function. Reduced drebrin has been found in the brain of patients with Alzheimer's disease or Down's syndrome. To examine whether the down-regulation of drebrin protein levels causes deficits in higher brain function, such as memory or cognition, we performed antisense-induced knockdown of drebrin A expression in rat brain using an hemagglutinating virus of Japan (HVJ)-liposome gene transfer technique. We investigated the effects of drebrin in vivo knockdown on spatial memory in a water-maze task, sensorimotor gating in a pre-pulse-inhibition test, adaptive behaviors in an open-field test, and sensitivity to psychostimulant in an amphetamine-induced locomotor response. Rats with drebrin A in vivo knockdown displayed a stronger preference for a previous event due to perseverative behavior, impaired pre-pulse inhibition (PPI), increased locomotor activity, anxiety-like behavior, and an increased sensitivity to psychostimulant, suggesting behaviors related to schizophrenia. These findings indicated that decreased drebrin produces deficits in cognitive function but not in spatial memory, probably via hypofunction of dendritic spines.


Subject(s)
Maze Learning/drug effects , Motor Activity/drug effects , Neural Inhibition/drug effects , Neuropeptides/antagonists & inhibitors , Oligonucleotides, Antisense/pharmacology , Adaptation, Psychological/physiology , Amphetamine/pharmacology , Analysis of Variance , Animals , Animals, Genetically Modified , Behavior, Animal , Blotting, Western/methods , Brain/drug effects , Brain/metabolism , Central Nervous System Stimulants/pharmacology , Gene Transfer, Horizontal , Genetic Vectors , Injections, Intraventricular/methods , Liposomes/metabolism , Male , Maze Learning/physiology , Motor Activity/physiology , Neural Inhibition/physiology , Neuropeptides/deficiency , Neuropeptides/genetics , Oligonucleotides, Antisense/administration & dosage , Rats , Rats, Wistar , Reflex, Startle/physiology , Sendai virus/genetics , Time Factors
9.
Brain Res ; 987(2): 194-200, 2003 Oct 17.
Article in English | MEDLINE | ID: mdl-14499963

ABSTRACT

To examine the role of mGluR1 (a subunit of the group I metabotropic glutamate receptor) in the nociceptive responses of rats following a subcutaneous injection of formalin into the plantar surface of the hind paw, we delivered antisense oligonucleotides (ODNs) against mGluR1 into the rat lumbar spinal cord (L3-L5) intrathecally using an HVJ-liposome-mediated gene transfer method. Rats treated with a single injection of mGluR1 antisense ODNs into the intrathecal space of the lumbar spinal cord showed a marked reduction of the early-sustained phase of formalin-induced nociceptive responses, but not of their acute phase. The reduction of nociceptive behavioral responses became apparent at day 2 after the antisense treatment and lasted for 2 days. This corresponded to a long-lasting down-regulation (46%) of mGluR1 expression in the lumbar cord. This down-regulated mGluR1 was observed at day 2 and persisted until day 4 after the intrathecal infusion of mGluR1 antisense ODN. In contrast, rats treated with mGluR1 sense or mismatch ODNs showed none of these changes. These results suggest that mGluR1 may play a crucial role in the sustained nociception of formalin-induced behavioral responses.


Subject(s)
Oligonucleotides, Antisense/administration & dosage , Pain Measurement/drug effects , Receptors, Metabotropic Glutamate/biosynthesis , Receptors, Metabotropic Glutamate/deficiency , Spinal Cord/metabolism , Animals , Down-Regulation/drug effects , Down-Regulation/physiology , Gene Transfer Techniques , Male , Oligonucleotides, Antisense/genetics , Pain Measurement/methods , Rats , Rats, Wistar , Receptors, Metabotropic Glutamate/genetics , Spinal Cord/drug effects
10.
Neurosci Res ; 46(1): 41-51, 2003 May.
Article in English | MEDLINE | ID: mdl-12725911

ABSTRACT

To examine the role of Ca(2+) entry through AMPA receptors in the pathogenesis of the ischemia-induced cell death of hippocampal neurons, we delivered cDNA of Q/R site-unedited form (GluR2Q) of AMPA receptor subunit GluR2 in the hippocampus by using an HVJ-liposome-mediated gene transfer technique. Two days prior to transient forebrain ischemia, we injected an HVJ-liposome containing cDNA of the GluR2Q-myc fusion gene into a rat unilateral hippocampus. In the absence of ischemic insult, overexpression of Ca(2+)-permeable GluR2Q did not cause any neurodegeneration in the cDNA-injected hippocampus. In ischemic rats, overexpression of Ca(2+)-permeable GluR2Q markedly promoted ischemic cell death of CA1 pyramidal neurons, while complete rescue of CA1 pyramidal neurons from ischemic damage occurred in the hippocampal hemisphere opposite the GluR2Q expression. Overexpression of the Q/R-site edited form (GluR2R) of subunit GluR2 did not affect the ischemia-induced damage of CA1 pyramidal neurons. From these results, we suggest that the Ca(2+)-permeability of AMPA receptors does not have a direct contribution to glutamate receptor-mediated neurotoxicity but has a promotive action in the evolution of ischemia-induced neurodegeneration of vulnerable neurons.


Subject(s)
Brain Ischemia/physiopathology , Calcium/metabolism , Nerve Degeneration/physiopathology , Pyramidal Cells/pathology , Receptors, AMPA/biosynthesis , Animals , Cell Death/physiology , Functional Laterality , Gene Transfer Techniques , Genes, myc/physiology , Genetic Vectors , Immunohistochemistry , Liposomes , Male , Nerve Degeneration/pathology , Pyramidal Cells/metabolism , Rats , Rats, Wistar , Receptors, AMPA/administration & dosage
11.
Neurosci Res ; 45(4): 473-81, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12657460

ABSTRACT

Considerable evidence suggests that an N-methyl-D-aspartate (NMDA) receptor plays a crucial role in memory and cognitive function. To identify the role of this receptor in higher functions of the brain, we delivered antisense oligonucleotides against an NMDA-NR1 subunit (NR1) to the hippocampus in rats using the HVJ-liposome-mediated gene-transfer method. NR1 hippocampal knockdown was performed by the focal injection of the NR1 antisense-HVJ-liposome complex into the bilateral hippocampus. The blocking effect of NR1-antisense on the expression of NR1 was confirmed by Western blot analysis. Spatial memory was tested by a water maze task, and sensorimotor gating was examined by prepulse inhibition (PPI). Western blot analysis demonstrated that the NR1-antisense treatment specifically provided the down-regulation (about 30%) of NR1 protein levels in the hippocampus. The water maze task showed that the antisense treatment did not affect spatial memory, while the PPI test revealed that NR1 hippocampal knockdown caused a deficit in sensorimotor gating. We conclude that mild dysfunction of hippocampal NMDA receptor causes sensorimotor gating deficit and relatively intact in spatial memory.


Subject(s)
Hippocampus/physiology , Maze Learning/physiology , Memory/physiology , Motor Activity/physiology , Receptors, N-Methyl-D-Aspartate/genetics , Animals , Animals, Genetically Modified , Down-Regulation , Gene Transfer Techniques , Gene Transfer, Horizontal , Genetic Vectors , Injections, Intraventricular , Liposomes , Male , Motor Activity/genetics , Oligonucleotides, Antisense/administration & dosage , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/metabolism , Sendai virus/genetics , Thionucleotides/genetics
12.
Neurosci Res ; 45(3): 285-96, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12631464

ABSTRACT

Neurotransmitter release during and after ischemic event is thought to be involved in excitotoxicity as a pathogenesis for the ischemic brain damage, which is mediated by excessive activation of glutamate receptors and attendant calcium overload. To ascertain the role of transmitter release from nerve terminals in promoting the ischemic neurodegeneration, we delivered antisense oligodeoxynucleotides (ODNs) to synaptotagmin I or synapsin I into the rat brain by using HVJ-liposome gene transfer technique. The antisense ODNs were injected into the lateralventricle in rats 4 days prior to transient forebrain ischemia of 20 min. With a single antisense treatment, long-lasting downregulation of the transmitter release relating protein levels at overall synaptic terminals was achieved. The antisense in vivo knockdown of synaptotagmin I prevented almost completely the ischemic damage of hippocampal CA1 neurons, while the in vivo knockdown of synapsin I markedly promoted the ischemic damage of CA1 pyramidal neurons and extended the injury to relatively resistant CA2/CA3 region. The modulation of ischemic hippocampal damage by the in vivo knockdown of synaptotagmin I or synapsin I suggests that transmitter release from terminals plays an important role in the evolution of ischemic brain damage and therefore the transmitter release strategy by the use of antisense ODNs-HVJ-liposome complex is reliable for neuroprotective therapies.


Subject(s)
Brain Ischemia/prevention & control , Calcium-Binding Proteins , Gene Transfer Techniques , Hippocampus/metabolism , Membrane Glycoproteins/deficiency , Nerve Tissue Proteins/deficiency , Oligonucleotides, Antisense/administration & dosage , Synapsins/deficiency , Animals , Brain Ischemia/genetics , Brain Ischemia/pathology , Down-Regulation/genetics , Down-Regulation/physiology , Hippocampus/pathology , Liposomes/administration & dosage , Membrane Glycoproteins/genetics , Nerve Tissue Proteins/genetics , Oligonucleotides, Antisense/genetics , Pyramidal Cells/metabolism , Pyramidal Cells/pathology , Rats , Synapsins/genetics , Synaptotagmin I , Synaptotagmins
13.
Neurosci Res ; 44(4): 455-65, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12445633

ABSTRACT

We have previously demonstrated that an acute pharmacological interruption of the afferent inputs from the hypothalamus to the hippocampus resulted in the blockade of the genesis and spread of intra-amygdala kainate-induced seizure activity in the hippocampus. This finding suggests that a sustained interruption of the hypothalamic stimulative influences may completely prevent amygdaloid seizure-induced hippocampal neuron damage. To test this assumption, we delivered antisense oligodeoxynucleotides (ODNs) against synaptotagmin I, a regulatory protein of the transmitter release machinery, into the hypothalamus by using a Hemagglutinating virus of Japan (HVJ)-liposome-mediated gene transfer technique. Four days prior to the induction of status epilepticus by intra-amygdala injection of kainate, the synaptotagmin I antisense was injected into the supramammillary nucleus (SuM) of the hypothalamus to chronically suppress the stimulative influences to the hippocampus via the reduction of transmitter release. The synaptotagmin I hypothalamic knockdown resulted in the almost complete prevention of seizure-induced damage of hippocampal neurons but not of entorhinal neurons following the kainate-induced amygdaloid seizures. This result suggests that the hypothalamic stimulative influences to the hippocampus have a major contribution to the amygdaloid seizure-induced hippocampal sclerosis, probably via disinhibition mechanism.


Subject(s)
Calcium-Binding Proteins , Entorhinal Cortex/metabolism , Epilepsy, Temporal Lobe/metabolism , Hippocampus/metabolism , Hypothalamus/metabolism , Membrane Glycoproteins/metabolism , Nerve Tissue Proteins/metabolism , Neural Pathways/metabolism , Neurons/metabolism , Amygdala/physiopathology , Animals , Disease Models, Animal , Down-Regulation/drug effects , Down-Regulation/physiology , Entorhinal Cortex/pathology , Entorhinal Cortex/physiopathology , Epilepsy, Temporal Lobe/pathology , Epilepsy, Temporal Lobe/physiopathology , Hippocampus/pathology , Hippocampus/physiopathology , Hypothalamus/cytology , Hypothalamus/drug effects , Kainic Acid , Male , Membrane Glycoproteins/antagonists & inhibitors , Nerve Tissue Proteins/antagonists & inhibitors , Neural Pathways/cytology , Neural Pathways/drug effects , Neurons/cytology , Neurons/drug effects , Oligonucleotides, Antisense/pharmacology , Rats , Rats, Wistar , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , Synaptotagmin I , Synaptotagmins
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