2006 — 2016 |
Braga, Maria F |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Efficacy of Glur5 Antogonists Against Soman-Induced Seizures and Neuropathology @ Henry M. Jackson Fdn For the Adv Mil/Med
[unreadable] DESCRIPTION (provided by applicant): Nerve agents are organophosphates with high toxicity, whose primary action is the irreversible inhibition of acetylcholinesterase. Clinical manifestations following nerve-agent exposure include the development of convulsive seizures, which can cause profound brain damage, resulting in death, or long-term cognitive deficits. At present, there are no prophylactic treatments that can effectively protect against nerve agent induced seizures, without causing significant side effects. Currently available post-exposure treatments can prevent death, but their efficacy in preventing seizures and associated brain damage has not been satisfactory. After exposure to a nerve agent, seizures are initiated primarily due to hyper-stimulation of muscarinic receptors. Cholinergic hyper-stimulation triggers glutamatergic hyperactivity, which intensifies and sustains seizures, and is ultimately responsible for neuronal damage. Therefore, anti-glutamatergic agents can be effective against seizures induced by cholinergic hyper-stimulation. Indeed, recent discoveries in the function of GluR5 kainate receptors (GluR5KRs, a kainate subtype of glutamate receptors containing the GluR5 subunit) have revealed that blockade of these receptors blocks epileptic seizures induced by the muscarinic agonist pilocarpine. As there are common mechanisms between pilocarpine-induced seizures and seizures induced by nerve agents, we hypothesize that antagonists of GluR5KRs will also be effective against nerve agent-induced seizures. The animal model we propose to use to test our hypothesis is in vivo exposure of rats to soman, as well as in vitro exposure of rat amygdala and hippocampal slices to soman. The selective GluR5KR antagonists LY293558 and UBP302 will be administered as a prophylactic treatment before exposure to soman, or as a therapy at different time points post-exposure. The efficacy of these antagonists against seizures will be correlated with their efficacy in preventing brain pathology, as well as pathophysiological alterations in the amygdala and hippocampus, studied in vitro after in vivo exposure to soman. The in vitro experiments will be performed in the amygdala and hippocampus because these brain regions play a pivotal role in the generation of brain seizures, including seizures induced by nerve agents. Furthermore, GluR5KRs play an important role in the regulation of neuronal excitability in the hippocampus, as well as in the amygdala, where we have found that strong activation of GluR5KRs inhibits evoked GABA release, and induces epileptiform activity. Because antagonists of GluR5KRs do not affect normal synaptic transmission, and the distribution of GluR5KRs in the brain is relatively limited, treatment with GluR5KR antagonists is likely to produce minimal or no side effects. Thus, the proposed investigations may result in the development of a novel, safe and effective prophylactic and/or therapeutic treatment against nerve agent-induced brain damage that will enhance our treatment response capabilities during an emergency. [unreadable] [unreadable] [unreadable]
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0.913 |
2015 — 2016 |
Braga, Maria F. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Targeting the Glutamatergic System to Counteract Soman Toxicity in Immature Rats @ Henry M. Jackson Fdn For the Adv Mil/Med
? DESCRIPTION (provided by applicant): Nerve agents are potent, organophosphorus toxins that act primarily by inhibiting the activity of acetylcholinesterase. The resulting accumulation o acetylcholine at synaptic junctions produces peripheral cholinergic crisis, and, in the brain, induces seizures and status epilepticus (SE). Without timely pharmacological intervention, death will ensue, or if death is prevented but the SE is not controlled, brain damage will result, with long-term neurological and behavioral consequences. The devastating effects of the sarin attack in Syria, in August of 2013, where 1,400 civilians were killed, 426 of which were children, brought again to the forefront the question of readiness and whether the existing medical countermeasures can save lives and protect against the long-term health consequences of exposure. Although the American Academy of Pediatrics have pointed out the reasons that children are more vulnerable to nerve agent toxicity, there is very little information on the appropriate countermeasures to protect the pediatric population, as data in immature animals are lacking. Here, we propose to test the combination of LY293558, an AMPA/GluR5(GluK1) receptor antagonist, with caramiphen (CRM), an antimuscarinic with NMDA receptor antagonistic properties, against soman-induced seizures, brain damage, behavioral deficits, and pathophysiological alterations in brain regions that underlie these deficits, in 12-day-old and 21-day-old rats. We have previously found that LY293558 and CRM are efficacious anticonvulsant treatments in adult rats, with the LY293558 having a faster seizure- suppressing action and greater neuroprotective effects. Recently, we discovered that when LY293558 and CRM are administered in combination, the results are far superior to those obtained when each drug is given alone; seizures are terminated in less than 10 min, neuronal degeneration is completely prevented, and the rats appear absolutely healthy the next day and have no weight loss. Targeting the glutamatergic system in immature rats to prevent nerve agent toxicity, with the use of a combination therapy that adds an NMDA antagonist to LY293558, is likely to be a most efficacious treatment, considering the high NMDA receptor activity in the developing brain, and its role in excitotoxicity.
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0.913 |
2018 — 2020 |
Braga, Maria F. |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Antiglutamatergic Therapy to Protect the Immature Brain Against Nerve Agents @ Henry M. Jackson Fdn For the Adv Mil/Med
Nerve agents are lethal chemical weapons that have been used in war and in terrorist attacks, with devastating consequences; the possibility that they will be used again against civilians is presently very high. One of the clinical manifestations of exposure to nerve agents is seizure activity progressing to status epilepticus (SE) which can lead to death, or brain damage with long-term neurological and behavioral consequences. The American Academy of Pediatrics have pointed out the reasons that children may be more vulnerable to nerve agent toxicity; yet, there is very little information on the appropriate countermeasures to protect the pediatric population, as data in immature animals are lacking. The FDA has approved diazepam as the anticonvulsant treatment for nerve agent-induced SE, irrespective of the age of the victim. However, there is sufficient evidence indicating that diazepam does not have good neuroprotective efficacy, and, in the developing brain, it may worsen the injury induced by the SE. Animal data are, therefore, needed to provide knowledge on how to protect the immature brain from damage in the event of nerve agent exposure, taking into account that GABAA receptor-mediated activity can be excitatory in the developing brain, while glutamatergic activity and particularly the activity of NMDA receptors, which are well known for their role in excitotoxicity, is very pronounced. We have already demonstrated the efficacy of LY293558, an AMPA/GluK1 receptor antagonist, in stopping seizures and significantly reducing neuropathology and long-term deficits in adult rats exposed to soman. We have also tested the combination of LY293558 with caramiphen, an antimuscarinic with NMDA receptor antagonistic properties, and found that it terminates soman-induced seizures faster than LY293558 alone, provides full protection from neuronal damage in all brain regions examined, and the recovery of the animals is swift with no weight loss. In the present application, we propose to test and compare the efficacy of LY293558+caramiphen with that of LY293558 alone, and with two benzodiazepines, diazepam and midazolam, against soman, in male and female rats of postnatal age 7, 12, and 21 days; anticonvulsant treatments will be administered 1 h after soman exposure. We hypothesize that LY293558+caramiphen will provide more benefits than LY293558 alone, and will prove to be far superior to both diazepam and midazolam in stopping soman-induced seizures, preventing neuronal degeneration, neuronal loss, GABAergic interneuronal loss, atrophy and pathophysiological alterations in the amygdala and hippocampus, as well as cognitive, behavioral, and neurological deficits studied up to 6 months postexposure. The data acquired will contribute immensely in developing safe and efficacious countermeasures for protecting the lives of infants and children and prevent long-term morbidities.
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0.913 |