Persistent behavior deficits, neuroinflammation, and oxidative stress in a rat model of acute organophosphate intoxication

Guignet, Michelle; Dhakal, Kiran; Flannery, Brenna M.; Hobson, Brad; Żółkowska, Dorota; Dhir, Ashish; Bruun, Donald A.; Li, Shuyang; Wahab, Abdul; Harvey, Danielle; Silverman, Jill L.; Rogawski, Michael A.; Lein, Pamela J.

doi:10.1016/j.nbd.2019.03.019

Cited by 76 publications

(121 citation statements)

References 59 publications

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“…OP exposure, whether acute or chronic, has been known to cause cognitive and motor impairments. 15,[47][48][49] We and others have shown that DFP exposure causes persistent neuronal loss and neuroinflammation 14,49,54,55 in various brain regions that may play a role in motor and cognitive dysfunction. In the present study, we observed cognitive impairment at 10 days after exposure to DFP when compared with the naive control, which is similar to the findings in the same model that we had reported previously.…”

Section: Discussionmentioning

confidence: 99%

“…53 We and others have demonstrated a significant increase in CD68-immunopositive microglia in the rat DFP model. 14,49 Representative IBA1-and CD68-immunostained cells in the DG from the control, vehicle, and DPO groups are shown in Figure 5D. IBA1-positive microglia colabeled with CD68 were significantly upregulated in CA1, CA3, DG, and PC in the DFP-exposed vehicle-treated group when compared with the control (Fig.…”

Section: (A) Representative Images Of Brain Sections (Ca1 Hippocampusmentioning

confidence: 98%

“…DFP exposure in rats chronically activates astrocytes and microglia. 14,49,50 The reactive astrogliosis and microgliosis contribute to the generation of ROS/RNS, proinflammatory cytokines, and epileptogenesis. 14,51 Immunohistochemistry of brain sections for GFAP and IBA1 was performed to determine astrogliosis and microgliosis, respectively.…”

Section: Dpo Treatment Attenuates Activated Astrogliosis But Not Micmentioning

confidence: 99%

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Diapocynin, an NADPH oxidase inhibitor, counteracts diisopropylfluorophosphate‐induced long‐term neurotoxicity in the rat model

Putra

Gage

Sharma

et al. 2020

Annals of the New York Academy of Sciences

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Organophosphate (OP) nerve agents are a threat to both the military and civilians. OP exposure causes cholinergic crisis and status epilepticus (SE) because of irreversible inhibition of acetylcholinesterase that can be lifethreatening if left untreated. OP survivors develop long-term morbidity, such as cognitive impairment and motor dysfunction, because of oxidative stress and progressive neuroinflammation and neurodegeneration, which act as disease promoters. Current medical countermeasures (MCMs) do not mitigate these pathologies. Therefore, our goal was to target these disease promoters using diapocynin (DPO), an NADPH oxidase inhibitor, in addition to MCMs, in a rat diisopropylfluorophosphate (DFP) model. The DFP-intoxicated rats were treated with DPO (300 mg/kg, oral, six doses, 12-h intervals) or vehicle 2 h following behavioral SE termination with diazepam. The DPO treatment significantly rescued DFP-induced motor impairment and attenuated epileptiform spiking during the first 72 h after DFP exposure in severely seizing rats despite no difference in epileptiform spike rate between the vehicle and DPO groups in mild SE rats. DPO significantly reduced DFP-induced reactive astrogliosis, neurodegeneration, GP91 phox , glutathiolated protein, serum nitrite, and proinflammatory cytokines and chemokines, such as interleukins (ILs) IL-1α, IL-6, IL-2, IL-17A, leptin, and IP-10, in the hippocampus. Collectively, these data support a neuroprotective role of DPO in an OP-induced neurotoxicity model.

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Section: Discussionmentioning

confidence: 99%

Section: (A) Representative Images Of Brain Sections (Ca1 Hippocampusmentioning

confidence: 98%

Section: Dpo Treatment Attenuates Activated Astrogliosis But Not Micmentioning

confidence: 99%

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Diapocynin, an NADPH oxidase inhibitor, counteracts diisopropylfluorophosphate‐induced long‐term neurotoxicity in the rat model

Putra

Gage

Sharma

et al. 2020

Annals of the New York Academy of Sciences

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“…We and others have demonstrated that DFP-induced SE also initiates epileptogenesis in the majority of animals, which is manifested by SRS. [23][24][25][26][27] Animals subjected to chemoconvulsants, including DFP and other nerve agents, develop neuroinflammation and neurodegeneration. 25,[28][29][30][31] Sex differences, however, are underinvestigated in DFP-induced long-term neurotoxicity studies.…”

Section: Introductionmentioning

confidence: 99%

Sex as a biological variable in the rat model of diisopropylfluorophosphate‐induced long‐term neurotoxicity

Gage

Golden

Putra

et al. 2020

Annals of the New York Academy of Sciences

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Sex differences in response to neurotoxicant exposure that initiates epileptogenesis are understudied. We used telemetry-implanted male and female adult rats exposed to an organophosphate (OP) neurotoxicant, diisopropylflourophosphate (DFP), to test sex differences in the severity of status epilepticus (SE) and the development of spontaneous recurrent seizures (SRS). Females had significantly less severe SE and decreased epileptiform spikes compared with males, although females received a higher dose of DFP than males. The estrous stages had no impact on seizure susceptibility, but rats with severe SE had a significantly prolonged diestrus. A previously demonstrated disease-modifying agent, an inducible nitric oxide synthase inhibitor, 1400W, was tested in both sexes. None of the eight males treated with 1400W developed convulsive SRS during 4 weeks post-DFP exposure, while two of seven females developed convulsive SRS. Concerning gliosis and neurodegeneration, there were region-specific differences in the interaction between sex and SE severity. As SE severity influences epileptogenesis, and as females had significantly less severe SE, sex as a biological variable should be factored into the design of future OP nerve agent experiments while evaluating neurotoxicity and optimizing potential disease-modifying agents.

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“…Aside from measurements of learning and memory, assessments of interictal emotional behavior in rodents have relied heavily on phenotyping batteries (23)(24)(25) to identify features of "depression-related" or "anxiety-related" behavior extrapolated from assessments of behavioral despair (e.g., forced swim test) or exploration (e.g., open field / elevated plus maze tests). While these tests are certainly convenient and offer a reasonably high throughput, they are short in duration (5-10 minutes long) and are often measured during the biological night (when lights are on).…”

Section: Introductionmentioning

confidence: 99%

Home-cage Monitoring Ascertains Signatures of Ictal and Interictal Behavior In Mouse Models of Generalized Seizures

Jankovic

Kapadia

Krishnan

2019

Preprint

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Significance Statement: Epilepsy is a brain disorder characterized by a pervasively increased risk to develop epileptic seizures. Sadly, patients with epilepsy also experience high rates of anxiety, depression and other psychiatric symptoms that significantly increase overall disability. While many mouse models of seizures and epilepsy exist, we need improved techniques to measure how new treatments impact not only seizure occurrence, but also emotional changes that persist in between seizures. In this study, we apply the technique of home-cage monitoring to clarify precisely how spontaneous mouse behavior is altered in three distinct epilepsy models. Our work illustrates the importance of an ethologically centered appreciation of neuropsychiatric disability in mice and clarifies a new approach to the measurement of "seizure severity".

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Persistent behavior deficits, neuroinflammation, and oxidative stress in a rat model of acute organophosphate intoxication

Cited by 76 publications

References 59 publications

Diapocynin, an NADPH oxidase inhibitor, counteracts diisopropylfluorophosphate‐induced long‐term neurotoxicity in the rat model

Diapocynin, an NADPH oxidase inhibitor, counteracts diisopropylfluorophosphate‐induced long‐term neurotoxicity in the rat model

Sex as a biological variable in the rat model of diisopropylfluorophosphate‐induced long‐term neurotoxicity

Home-cage Monitoring Ascertains Signatures of Ictal and Interictal Behavior In Mouse Models of Generalized Seizures

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