Identification of neuronal target areas for nerve agents and specification of receptors for pharmacological treatment

Myhrer, Trond

doi:10.1016/j.neuro.2010.07.002

Cited by 22 publications

(10 citation statements)

References 71 publications

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“…However, civilians are unequipped to self-administer antidotes after an attack, and delays of at least 30 min may occur before emergency personnel can safely assess victims to provide initial treatments (Myhrer, 2010; Yanagisawa et al, 2006). Delaying treatment increases the incidence of neuropathology, as it has been observed in animal models of nerve agent exposure; seizures lasting 20 min cause brain damage in approximately 10% of animals, whereas 40 min of continuous seizures causes damage in approximately 79% of animals (McDonough et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Pathophysiological mechanisms underlying increased anxiety after soman exposure: Reduced GABAergic inhibition in the basolateral amygdala

et al. 2014

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The recent sarin attack in Syria killed 1,429 people, including 426 children, and left countless more to deal with the health consequences of the exposure. Prior to the Syrian chemical assault, nerve agent attacks in Japan left many victims suffering from neuropsychiatric illnesses, particularly anxiety disorders, more than a decade later. Uncovering the neuro-pathophysiological mechanisms underlying the development of anxiety after nerve agent exposure is necessary for successful treatment. Anxiety is associated with hyperexcitability of the basolateral amygdala (BLA). The present study sought to determine the nature of the nerve agent-induced alterations in the BLA, which could explain the development of anxiety. Rats were exposed to soman, at a dose that induced prolonged status epilepticus. Twenty-four hours and 14-days after exposure, neurons from the BLA were recorded using whole-cell patch-clamp techniques. At both the 24 h and 14-day post-exposure time-points, the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) in the BLA were reduced, along with reduction in the frequency but not amplitude of miniature IPSCs. In addition, activation of α7-nicotinic acetylcholine receptors, a cholinergic receptor that participates in the regulation of BLA excitability and is involved in anxiety, increased spontaneous excitatory postsynaptic currents (sEPSCs) in both soman-exposed rats and controls, but was less effective in increasing sIPSCs in soman-exposed rats. Despite the loss of both interneurons and principal cells after soman-induced status epilepticus, the frequency of sEPSCs was increased in the soman-exposed rats. Impaired function and cholinergic modulation of GABAergic inhibition in the BLA may underlie anxiety disorders that develop after nerve agent exposure.

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Section: Introductionmentioning

confidence: 99%

Pathophysiological mechanisms underlying increased anxiety after soman exposure: Reduced GABAergic inhibition in the basolateral amygdala

et al. 2014

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“…For rats exposed to VX via microinjection, the seizure appeared to initiate from within the limbic forebrain (McDonough et al 1993). Additional potential seizure initiation sites include the area tempestas, medial septum, and perirhinal cortex (Myhrer 2010). When studying the first phase of seizures in guinea pigs, O’Donnell et al (2011) noticed elevations in ACh and glutamate (GLU) levels in the brains of sarin-exposed animals.…”

Section: Sarin-induced Seizurementioning

confidence: 99%

“…Diazepam, however, also impairs attention and cognitive and psychomotor performance, specifically in critical flicker fusion threshold, decision-making, learning, and memory (McDonough 2002). Other seizure treatments look to target the specific sites of seizure initiation but, given that these regions vary by the type of OP administered and that each region responds to different pharmaceuticals, there is not a single treatment option that can offer complete OP protection (Myhrer 2010). …”

Section: Status Epilepticusmentioning

confidence: 99%

Sarin (GB, O-isopropyl methylphosphonofluoridate) neurotoxicity: critical review

Abou‐Donia

Siracuse

Gupta

et al. 2016

Critical Reviews in Toxicology

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Sarin (GB, O-isopropyl methylphosphonofluoridate) is a potent organophosphorus (OP) nerve agent that inhibits acetylcholinesterase (AChE) irreversibly. The subsequent build-up of acetylcholine (ACh) in the central nervous system (CNS) provokes seizures and, at sufficient doses, centrally-mediated respiratory arrest. Accumulation of ACh at peripheral autonomic synapses leads to peripheral signs of intoxication and overstimulation of the muscarinic and nicotinic receptors, which is described as “cholinergic crisis” (i.e. diarrhea, sweating, salivation, miosis, bronchoconstriction). Exposure to high doses of sarin can result in tremors, seizures, and hypothermia. More seriously, build-up of ACh at neuromuscular junctions also can cause paralysis and ultimately peripherally-mediated respiratory arrest which can lead to death via respiratory failure. In addition to its primary action on the cholinergic system, sarin possesses other indirect effects. These involve the activation of several neurotransmitters including gamma-amino-butyric acid (GABA) and the alteration of other signaling systems such as ion channels, cell adhesion molecules, and inflammatory regulators. Sarin exposure is associated with symptoms of organophosphate-induced delayed neurotoxicity (OPIDN) and organophosphate-induced chronic neurotoxicity (OPICN). Moreover, sarin has been involved in toxic and immunotoxic effects as well as organophosphate-induced endocrine disruption (OPIED). The standard treatment for sarin-like nerve agent exposure is post-exposure injection of atropine, a muscarinic receptor antagonist, accompanied by an oxime, an AChE reactivator, and diazepam.

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“…Pharmacological agents with potential anticonvulsant efficacy in the brain areas that have been identified as target sites for generation of seizures (the area tempestas, medial septum, perirhinal cortex, posterior piriform cortex) have been used in microinfusion studies (Myhrer, 2010). In the area tempestas, cholinergic, but not glutamatergic, antagonism is likely the active property of the anti-Parkinson agents, caramiphen and procyclidine, because the NMDA antagonists ketamine and MK-801 do not have anticonvulsant effects (Myhrer et al, 2008a).…”

Section: Animal Studiesmentioning

confidence: 99%

Prophylactic and Therapeutic Measures in Nerve Agents Poisoning

Myhrer¹,

Aas²

2015

Handbook of Toxicology of Chemical Warfare Agents

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Identification of neuronal target areas for nerve agents and specification of receptors for pharmacological treatment

Cited by 22 publications

References 71 publications

Pathophysiological mechanisms underlying increased anxiety after soman exposure: Reduced GABAergic inhibition in the basolateral amygdala

Pathophysiological mechanisms underlying increased anxiety after soman exposure: Reduced GABAergic inhibition in the basolateral amygdala

Sarin (GB, O-isopropyl methylphosphonofluoridate) neurotoxicity: critical review

Prophylactic and Therapeutic Measures in Nerve Agents Poisoning

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