Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental studies suggest that the delivery of antiepileptic agents into the seizure focus might be of potential utility for the treatment of focal-onset epilepsies. Botulinum neurotoxin E (BoNT/E) causes a prolonged inhibition of neurotransmitter release after its specific cleavage of the synaptic protein synaptosomal-associated protein of 25 kDa (SNAP-25). Here, we show that BoNT/E injected into the rat hippocampus inhibits glutamate release and blocks spike activity of pyramidal neurons. BoNT/E effects persist for at least 3 weeks, as determined by immunodetection of cleaved SNAP-25 and loss of intact SNAP-25. The delivery of BoNT/E to the rat hippocampus dramatically reduces both focal and generalized kainic acid-induced seizures as documented by behavioral and electrographic analysis. BoNT/E treatment also prevents neuronal loss and long-term cognitive deficits associated with kainic acid seizures. Moreover, BoNT/E-injected rats require 50% more electrical stimulations to reach stage 5 of kindling, thus indicating a delayed epileptogenesis. We conclude that BoNT/E delivery to the hippocampus is both antiictal and antiepileptogenic in experimental models of epilepsy.
 ...
PMID:Antiepileptic effects of botulinum neurotoxin E. 1572 34

Clinical and experimental studies clearly demonstrate that prolonged seizures and status epilepticus induce neuronal cell death in the brain. Recent evidence suggests that induction of apoptosis contributes greatly to seizure-induced brain damage. We recently demonstrated that intrahippocampal delivery of botulinum neurotoxin E (BoNT/E) in the rat hippocampus is able to prevent neuronal loss, which occurs after kainic-acid-induced seizures. Here, we investigated the molecular mechanisms of BoNT/E-mediated neuroprotection. We found that intrahippocampal administration of BoNT/E prevents the upregulation of apoptotic proteins (phosphorylated c-Jun and cleaved caspase 3), which occurs in hippocampal neurones following kainic acid seizures. These results demonstrate that the neuroprotective action of BoNT/E on seizure-injured hippocampal neurons involves the blockade of well-characterized apoptotic pathways.
 ...
PMID:BoNT/E prevents seizure-induced activation of caspase 3 in the rat hippocampus. 1741 60

Clinical and experimental studies clearly demonstrate that prolonged seizures and status epilepticus induce neuronal cell death in the brain. Recent evidence suggests that induction of apoptosis contributes greatly to seizure-induced brain damage. We recently demonstrated that intrahippocampal delivery of botulinum neurotoxin E (BoNT/E) in the rat hippocampus is able to prevent neuronal loss, which occurs after kainic-acid-induced seizures. Here, we investigated the molecular mechanisms of BoNT/E-mediated neuroprotection. We found that intrahippocampal administration of BoNT/E prevents the upregulation of apoptotic proteins (phosphorylated c-Jun and cleaved caspase 3), which occurs in hippocampal neurones following kainic acid seizures. These results demonstrate that the neuroprotective action of BoNT/E on seizure-injured hippocampal neurons involves the blockade of well-characterized apoptotic pathways.
 ...
PMID:BoNT/E prevents seizure-induced activation of caspase 3 in the rat hippocampus. 1744 Dec 89

Mesial temporal lobe epilepsy (MTLE) is often the result of an early insult that induces a reorganization in hippocampal circuitry leading, after a latent period, to chronic epilepsy. Hippocampal rearrangements during the latent phase include neuronal loss, axonal and dendritic plasticity, neurogenesis, and cell repositioning, but the role of these changes in epilepsy development is unclear. Here we have tested whether administration of the synaptic blocker botulinum neurotoxin E (BoNT/E) interferes with development of spontaneous seizures and histopathological changes following an episode of status epilepticus (SE). SE was induced by unilateral intrahippocampal injection of kainic acid in mice and BoNT/E was delivered to the same hippocampus 3 h later. We found that treatment with BoNT/E prolonged the duration of the latent period but did not block the occurrence of spontaneous seizures. At the histopathological level, BoNT/E reduced loss of CA1 pyramidal neurons and dispersion of dentate granule cells. Downregulation of reelin expression along the hippocampal fissure was also suppressed by BoNT/E treatment. Our findings indicate that administration of BoNT/E after SE inhibits specific morphological changes in hippocampal circuitry but not the development of spontaneous seizures. This indicates a dissociation between certain anatomical modifications and establishment of chronic epilepsy in MTLE.
 ...
PMID:Botulinum neurotoxin E (BoNT/E) reduces CA1 neuron loss and granule cell dispersion, with no effects on chronic seizures, in a mouse model of temporal lobe epilepsy. 1817 62

Mesial temporal lobe epilepsy (MTLE) is one of the most common forms of human epilepsy, and it is often resistant to conventional antiepileptic drug (AED) therapy. Here we tested whether a single intrahippocampal administration of the synaptic blocker botulinum neurotoxin E (BoNT/E) is effective in reducing spontaneous recurrent seizures (SRS) in a mouse model of MTLE. Unilateral intrahippocampal injection of kainic acid (KA) in mice was used as a model of MTLE. Electroencephalography (EEG) recordings of SRS were performed during the chronic phase of epilepsy, before and after administration of either BoNT/E or vehicle. Frequency of SRS was significantly decreased for at least 5 days following BoNT/E, but not vehicle, infusion. Our findings demonstrate that BoNT/E can effectively reduce seizure incidence in a mouse model of MTLE.
 ...
PMID:Intrahippocampal infusion of botulinum neurotoxin E (BoNT/E) reduces spontaneous recurrent seizures in a mouse model of mesial temporal lobe epilepsy. 1917 93

Epilepsy characterized by recurrent behavioral seizures, affects approximately 1% of the population worldwide. More than one-third of epilepsy patients are estimated to have pharmacoresistant epilepsy. One-half of patients with refractory epilepsy are characterized as having mesial TLE with foci in the amygdaloid complex, hippocampus, and surrounding cortex. In 50-70% of such cases, surgical removal of the temporal lobes can successfully treat the disease, however, it is not always applicable because of the presence of secondary foci and localization of primary foci in the deep brain. A recent therapeutic approach focuses on the delivery of botulinum neurotoxins directly into the seizure focus in the brain and this approach is currently being investigated using animal models. Several reports have demonstrated that botulinum neurotoxin E injected into the hippocampus of rat with KA-induced epileptic rats prevents neuronal loss in the CA1-subfield of the hippocampus and the dentate granule cell dispersions, and glutamate release from the hippocampal synaptosomes. Furthermore, injection following the acquirement of KA-induced spontaneous recurrent seizures reduces chronic seizures. We provide a plausible mechanism of action of botulinum neurotoxin action in the CNS and discuss the possibility of its therapeutic application to human epilepsy.
 ...
PMID:[Application of botulinum neurotoxin in the treatment of epilepsy]. 1969 83

This retrospective study aimed to examine the safety of botulinum toxin A (BoNT-A) treatment in a paediatric multidisciplinary cerebral palsy clinic. In a sample of 454 patients who had 1515 BoNT-A sessions, data on adverse events were available in 356 patients and 1382 sessions; 51 non-fatal adverse events were reported (3.3% of the total injections number, 8.7% of the patients). On five occasions, the adverse reactions observed in GMFCS V children were attributed to the sedation used (rectal midazolam plus pethidine; buccal midazolam) and resulted in prolongation of hospitalization. Of the reactions attributed to the toxin, 23 involved an excessive reduction of the muscle tone either of the injected limb(s) or generalized; others included local pain, restlessness, lethargy with pallor, disturbance in swallowing and speech production, seizures, strabismus, excessive sweating, constipation, vomiting, a flu-like syndrome and emerging hypertonus in adjacent muscles. Their incidence was associated with GMFCS level and with the presence of epilepsy (Odds ratio (OR) = 2.74 - p = 0.016 and OR = 2.35 - p = 0.046, respectively) but not with BoNT-A dose (either total or per kilogram). In conclusion, treatment with BoNT-A was safe; adverse reactions were mostly mild even for severely affected patients. Their appearance did not necessitate major changes in our practice.
 ...
PMID:Safety of botulinum toxin A in children and adolescents with cerebral palsy in a pragmatic setting. 2348 50

Botulinum neurotoxins are metalloproteases that specifically cleave N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in synaptic terminals, resulting in a potent inhibition of vesicle fusion and transmitter release. The family comprises different serotypes (BoNT/A to BoNT/G). The natural target of these toxins is represented by the neuromuscular junction, where BoNTs block acetylcholine release. In this review, we describe the actions of botulinum toxins after direct delivery to the central nervous system (CNS), where BoNTs block exocytosis of several transmitters, with near-complete silencing of neural networks. The use of clostridial neurotoxins in the CNS has allowed us to investigate specifically the role of synaptic activity in different physiological and pathological processes. The silencing properties of BoNTs can be exploited for therapeutic purposes, for example to counteract pathological hyperactivity and seizures in epileptogenic brain foci, or to investigate the role of activity in degenerative diseases like prion disease. Altogether, clostridial neurotoxins and their derivatives hold promise as powerful tools for both the basic understanding of brain function and the dissection and treatment of activity-dependent pathogenic pathways.
 ...
PMID:Exploiting Botulinum Neurotoxins for the Study of Brain Physiology and Pathology. 2969

Botulinum neurotoxins (BoNTs) block the release of a series of neurotransmitters, which are pivotal for neuron action. Intrahippocampal administration of BoNTs inhibits glutamate release, protects neurons against cell death, and attenuates epileptic seizures. Compared with intrahippocampal administration, intranasal delivery is less invasive and more practical for chronic drug administration. To assess whether intranasal administration is feasible, we examined the role of botulinum neurotoxin A (BoNT/A) in hippocampal neuronal injury after status epilepticus (SE) induced by pilocarpine. Our data showed BoNT/A could bypass the blood-brain barrier (BBB) and entered the olfactory bulb and hippocampal neurons. In addition, SE could result in up-regulation of pro-apoptotic proteins (Caspase-3, Bax), down-regulation of anti-apoptotic protein Bcl-2 and neuronal death in hippocampus. BoNT/A could suppress the expression of Caspase-3 and Bax, attenuate the decrease of Bcl-2, and inhibit hippocampal neuron death induced by SE. Meanwhile, there was no significant difference in cognitive behavior between the BoNT/A-pretreated rats and normal rats. Thus, we provided a more convenient and less invasive route for taking advantage of BoNT/A in the field of anti-epilepsy.
 ...
PMID:Intranasal Delivery of Botulinum Neurotoxin A Protects against Hippocampal Neuron Death in the Lithium-Pilocarpine Rat Model. 3087 18