Maria F. M. Braga

Uniformed Services University of the Health Sciences

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Vassiliki Aroniadou‐Anderjaska

Uniformed Services University of the Health Sciences

Taíza H. Figueiredo

Uniformed Services University of the Health Sciences

James P. Apland

United States Army

Volodymyr I. Pidoplichko

Uniformed Services University of the Health Sciences

Eric M. Prager

Regeneron (United States)

Camila P. Almeida-Suhett

Uniformed Services University of the Health Sciences

Ann M. Marini

Uniformed Services University of the Health Sciences

Felicia Qashu

National Institutes of Health

Edna F.R. Pereira

University of Maryland, Baltimore

Marcio de Araujo Furtado

Uniformed Services University of the Health Sciences

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Ministério da Saúde

173

Uniformed Services University of the Health Sciences

National Institutes of Health

Universidade de São Paulo

Pediatrics and Genetics

Universidade Federal do Rio de Janeiro

National Institute of Mental Health

United States Army

Autoliv (Sweden)

Center for Neuroscience and Regenerative Medicine

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Pb²⁺ via Protein Kinase C Inhibits Nicotinic Cholinergic Modulation of Synaptic Transmission in the Hippocampus

Journal of Pharmacology and Experimental Therapeutics (2004)

Maria F. M. Braga Edna F. R. Pereira Árpád Mike Edson X. Albuquerque

The present study was designed to investigate the effects of Pb²⁺ on modulation of synaptic transmission by nicotinic receptors (nAChRs) in the rat hippocampus. To this end, inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs, respectively) were recorded by means of the whole-cell mode of the patch-clamp technique from rat hippocampal neurons in culture. Acetylcholine (ACh, 1 mM; 1-s pulses) triggered GABA release via activation of α4β2^* and α7^* nAChRs. It also triggered glutamate release via activation of α7^* nAChRs. Pb²⁺ (0.1 and 1 μM) blocked ACh-triggered transmitter release. Blockade by Pb²⁺ of ACh-triggered IPSCs was partially reversible upon washing of the neurons. In contrast, even after 30- to 60-min washing, there was no reversibility of Pb²⁺-induced blockade of ACh-triggered EPSCs. The effects of Pb²⁺ on GABA release triggered by activation of α7^* and α4β2^* nACRs were mimicked by the protein kinase C (PKC) activator phorbol-12-myristate-13-acetate (1 μM) and blocked by the indolocarbazole Gö 7874 (50 nM) and the bisindolylmaleimide Ro-31-8425 (150 nM), which are selective PKC inhibitors. After washing of fully functional neuronal networks that had been exposed for 5 min to Pb²⁺, the irreversible inhibition by Pb²⁺ of ACh-triggered glutamate release was partially overridden by a disinhibitory mechanism that is likely to involve α4β2^* nAChR activation in interneurons that synapse onto other interneurons synapsing onto pyramidal neurons. Long-lasting inhibition of α7^* nAChR modulation of synaptic transmission may contribute to the persistent cognitive impairment that results from childhood Pb²⁺ intoxication.

10.1124/jpet.104.070466

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Citations (22)

Delayed tezampanel and caramiphen treatment but not midazolam protects against long-term neuropathology after soman exposure

Experimental Biology and Medicine (2023)

Taíza H. Figueiredo Vassiliki Aroniadou‐Anderjaska James P. Apland Katia Rossetti Maria F. M. Braga

Prolonged status epilepticus (SE) can cause brain damage; therefore, treatment must be administered promptly after seizure onset to limit SE duration and prevent neuropathology. Timely treatment of SE is not always feasible; this would be particularly true in a mass exposure to an SE-inducing agent such as a nerve agent. Therefore, the availability of anticonvulsant treatments that have neuroprotective efficacy even if administered with a delay after SE onset is an imperative. Here, we compared the long-term neuropathology resulting from acutely exposing 21-day-old male and female rats to the nerve agent soman, and treating them with midazolam (3 mg/kg) or co-administration of tezampanel (10 mg/kg) and caramiphen (50 mg/kg), at 1 h postexposure (~50 min after SE onset). Midazolam-treated rats had significant neuronal degeneration in limbic structures, mainly at one month postexposure, followed by neuronal loss in the basolateral amygdala and the CA1 hippocampal area. Neuronal loss resulted in significant amygdala and hippocampal atrophy, deteriorating from one to six months postexposure. Rats treated with tezampanel–caramiphen had no evidence of neuropathology, except for neuronal loss in the basolateral amygdala at the six-month timepoint. Anxiety was increased only in the midazolam-treated rats, at one, three, and six months postexposure. Spontaneous recurrent seizures appeared only in midazolam-treated rats, at three and six months postexposure in males and only at six months in females. These findings suggest that delayed treatment of nerve agent–induced SE with midazolam may result in long-lasting or permanent brain damage, while antiglutamatergic anticonvulsant treatment consisting of tezampanel and caramiphen may provide full neuroprotection.

Neuropathology

Basolateral amygdala

Midazolam

Convulsion

Brain damage

10.1177/15353702231171911

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Citations (7)

Long‐term neuropathological and behavioral impairments after exposure to nerve agents

Annals of the New York Academy of Sciences (2016)

Vassiliki Aroniadou‐Anderjaska Taíza H. Figueiredo James P. Apland Eric M. Prager Volodymyr I. Pidoplichko

One of the deleterious effects of acute nerve agent exposure is the induction of status epilepticus (SE). If SE is not controlled effectively, it causes extensive brain damage. Here, we review the neuropathology observed after nerve agent‒induced SE, as well as the ensuing pathophysiological, neurological, and behavioral alterations, with an emphasis on their time course and longevity. Limbic structures are particularly vulnerable to damage by nerve agent exposure. The basolateral amygdala (BLA), which appears to be a key site for seizure initiation upon exposure, suffers severe neuronal loss; however, GABAergic BLA interneurons display a delayed death, perhaps providing a window of opportunity for rescuing intervention. The end result is a long‐term reduction of GABAergic activity in the BLA, with a concomitant increase in spontaneous excitatory activity; such pathophysiological alterations are not observed in the CA1 hippocampal area, despite the extensive neuronal loss. Hyperexcitability in the BLA may be at least in part responsible for the development of recurrent seizures and increased anxiety, while hippocampal damage may underlie the long‐term memory impairments. Effective control of SE after nerve agent exposure, such that brain damage is also minimized, is paramount for preventing lasting neurological and behavioral deficits.

Neuropathology

Basolateral amygdala

Brain damage

10.1111/nyas.13028

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Citations (42)

Full Protection Against Soman-Induced Seizures and Brain Damage by LY293558 and Caramiphen Combination Treatment in Adult Rats

Neurotoxicity Research (2018)

James P. Apland Vassiliki Aroniadou‐Anderjaska Taíza H. Figueiredo Marcio de Araujo Furtado Maria F. M. Braga

Convulsion

Brain damage

10.1007/s12640-018-9907-1

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Citations (20)

Alterations in GABAA receptor-mediated inhibition triggered by status epilepticus and their role in epileptogenesis and increased anxiety

Neurobiology of Disease (2024)

Vassiliki Aroniadou‐Anderjaska Taíza H. Figueiredo Marcio de Araujo Furtado Volodymyr I. Pidoplichko Lucille A. Lumley

The triggers of status epilepticus (SE) in non-epileptic patients can vary widely, from idiopathic causes to exposure to chemoconvulsants. Regardless of its etiology, prolonged SE can cause significant brain damage, commonly resulting in the development of epilepsy, which is often accompanied by increased anxiety. GABA

10.1016/j.nbd.2024.106633

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Citations (2)

The Recovery of GABAergic Function in the Hippocampus CA1 Region After mTBI

Molecular Neurobiology (2019)

Taíza H. Figueiredo Carolina L. Harbert Volodymyr I. Pidoplichko Camila P. Almeida-Suhett Katia Rossetti

Neurocognitive

Stereology

10.1007/s12035-019-01753-z

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Citations (7)

Soman induces ictogenesis in the amygdala and interictal activity in the hippocampus that are blocked by a GluR5 kainate receptor antagonist in vitro

Neuroscience (2008)

James P. Apland Vassiliki Aroniadou‐Anderjaska Maria F. M. Braga

Kainate receptor

Basolateral amygdala

10.1016/j.neuroscience.2008.11.053

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Citations (28)

The M₁ Muscarinic Receptor Antagonist VU0255035 Delays the Development of Status Epilepticus after Organophosphate Exposure and Prevents Hyperexcitability in the Basolateral Amygdala

Journal of Pharmacology and Experimental Therapeutics (2016)

Steven L. Miller Vassiliki Aroniadou‐Anderjaska Volodymyr I. Pidoplichko Taíza H. Figueiredo James P. Apland

Exposure to organophosphorus toxins induces seizures that progress to status epilepticus (SE), which can cause brain damage or death. Seizures are generated by hyperstimulation of muscarinic receptors, subsequent to inhibition of acetylcholinesterase; this is followed by glutamatergic hyperactivity, which sustains and reinforces seizure activity. It has been unclear which muscarinic receptor subtypes are involved in seizure initiation and the development of SE in the early phases after exposure. Here, we show that pretreatment of rats with the selective M₁ receptor antagonist, VU0255035 [N-(3-oxo-3-(4-(pyridine-4-yl)piperazin-1-yl)propyl)-benzo[c][1,2,5]thiadiazole-4 sulfonamide], significantly suppressed seizure severity and prevented the development of SE for about 40 minutes after exposure to paraoxon or soman, suggesting an important role of the M₁ receptor in the early phases of seizure generation. In addition, in in vitro brain slices of the basolateral amygdala (a brain region that plays a key role in seizure initiation after nerve agent exposure), VU0255035 blocked the effects produced by bath application of paraoxon—namely, a brief barrage of spontaneous inhibitory postsynaptic currents, followed by a significant increase in the ratio of the total charge transferred by spontaneous excitatory postsynaptic currents over that of the inhibitory postsynaptic currents. Furthermore, paraoxon enhanced the hyperpolarization-activated cation current I_h in basolateral amygdala principal cells, which could be one of the mechanisms underlying the increased glutamatergic activity, an effect that was also blocked in the presence of VU0255035. Thus, selective M₁ antagonists may be an efficacious pretreatment in contexts in which there is risk for exposure to organophosphates, as these antagonists will delay the development of SE long enough for medical assistance to arrive.

Basolateral amygdala

Methoctramine

Paraoxon

10.1124/jpet.116.236125

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Citations (23)

Diazepam administration after prolonged status epilepticus reduces neurodegeneration in the amygdala but not in the hippocampus during epileptogenesis

Amino Acids (2009)

Felicia Qashu Taíza H. Figueiredo Vassiliki Aroniadou‐Anderjaska James P. Apland Maria F. M. Braga

Piriform cortex

Limbic system

10.1007/s00726-008-0227-2