Role of Gaba Receptor Complex in Low Dose Lindane (HCH) Induced Neurotoxicity: Neurobehavioural, Neurochemical and Electrophysiological Studies

Anand, M.; Agrawal, A.K.; Rehmani, B. N. H.; Gupta, Garima; Rana, Michele; Seth, Prahlad K.

doi:10.3109/01480549809017849

Cited by 38 publications

(17 citation statements)

References 18 publications

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“…It may be of prolonged duration (years) and is exceedingly prevalent among chemical workers chronically exposed, with up to 67% variably affected in some studies 69–71. In laboratory animals, OCPs may reduce brain GABA concentrations72 and bind to and inhibit the GABA(A) receptor in the brain,73–75 the same receptor complex that has been implicated in the etiology of ET 56. In dogs, some OCPs produce parenchymatous degeneration in the cerebellar cortex,76 the brain region which may be involved in the pathogenesis of ET 36–38…”

Section: Nature Vs Nurturementioning

confidence: 99%

A Stable Chemical SUMO1–Ubc9 Conjugate Specifically Binds as a Thioester Mimic to the RanBP2–E3 Ligase Complex

et al. 2015

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Ubiquitin and ubiquitin-like (Ubl) modifiers such as SUMO are conjugated to substrate proteins by E1, E2, and E3 enzymes. In the presence of an E3 ligase, the E2∼Ubl thioester intermediate becomes highly activated and is prone to chemical decomposition, thus making biochemical and structural studies difficult. Here we explored a stable chemical conjugate of the E2 enzyme from the SUMO pathway, Ubc9, with its modifier SUMO1 as a structural analogue of the Ubc9∼SUMO1 thioester intermediate, by introducing a triazole linkage by biorthogonal click chemistry. The chemical conjugate proved stable against proteolytic cleavage, in contrast to a Ubc9-SUMO1 isopeptide analogue obtained by auto-SUMOylation. Triazole-linked Ubc9-SUMO1 bound specifically to the preassembled E3 ligase complex RanBP2/RanGAP1*SUMO1/Ubc9, thus suggesting that it is a suitable thioester mimic. We anticipate interesting prospects for its use as a research tool to study protein complexes involving E2 and E3 enzymes.

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Section: Nature Vs Nurturementioning

confidence: 99%

A Stable Chemical SUMO1–Ubc9 Conjugate Specifically Binds as a Thioester Mimic to the RanBP2–E3 Ligase Complex

et al. 2015

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“…In zebrafish, it has been reported that ethanol causes abnormal development of motor neurons and muscle fibers [25]. The neurotoxic effect of lindane has also been well documented [26], [44] and chronic exposure of low dose lindane causes neurobehavioral, neurochemical, and electrophysiologrcal efects in rat brain [45].…”

Section: Discussionmentioning

confidence: 99%

Fluorescent Transgenic Zebrafish Tg(nkx2.2a:mEGFP) Provides a Highly Sensitive Monitoring Tool for Neurotoxins

Zhang

Gong

2013

PLoS ONE

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Previously a standard toxicological test termed as DarT (Danio rerio Teratogenic assay) using wild type zebrafish embryos has been established and it is widely applied in toxicological and chemical screenings. As an increasing number of fluorescent transgenic zebrafish lines with specific fluorescent protein expression specifically expressed in different organs and tissues, we envision that the fluorescent markers may provide more sensitive endpoints for monitoring chemical induced phenotypical changes. Here we employed Tg(nkx2.2a:mEGFP) transgenic zebrafish which have GFP expression in the central nervous system to investigate its potential for screening neurotoxic chemicals. Five potential neurotoxins (acetaminophen, atenolol, atrazine, ethanol and lindane) and one neuroprotectant (mefenamic acid) were tested. We found that the GFP-labeled ventral axons from trunk motoneurons, which were easily observed in live fry and measured for quantification, were a highly sensitive to all of the five neurotoxins and the length of axons was significantly reduced in fry which looked normal based on DarT endpoints at low concentrations of neurotoxins. Compared to the most sensitive endpoints of DarT, ventral axon marker could improve the detection limit of these neurotoxins by about 10 fold. In contrast, there was no improvement for detection of the mefenamic acid compared to all DarT endpoints. Thus, ventral axon lengths provide a convenient and measureable marker specifically for neurotoxins. Our study may open a new avenue to use other fluorescent transgenic zebrafish embryos/fry to develop sensitive and specific toxicological tests for different categories of chemicals.

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“…Several mechanisms underlying the lindane seizures have been proposed [8] . First of all, lindane binds to the picrotoxin site within the GABA A chloride channel and suppresses the transmembrane influx of chloride ions [6,7] . Further, it has been postulated that lindane could produce its neurotoxic effects through intracellular mobilization of calcium from the dantrolene-sensitive pools and calcium influx [23,24] .…”

Section: Discussionmentioning

confidence: 99%

“…Seizures are one of the first and main manifestations of the neurotoxic effects of lindane in humans and animals [4,5] . Lindane evokes seizures mainly through the blockade of the ␥ -aminobutyric acid A (GABA A ) receptor complex [6][7][8] . Lindane-induced seizures are refractory to numerous classical and novel antiepileptic drugs [9] .…”

Section: Introductionmentioning

confidence: 99%

Influence of NR2B-Selective NMDA Antagonist on Lindane-Induced Seizures in Rats

et al. 2009

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Ifenprodil is a novel NMDA receptor antagonist that selectively inhibits receptors containing the NR2B subunit. Lindane, a widely used pesticide and scabicide, evokes seizures mainly through the blockade of the γ-aminobutyric acid type A receptor complex. The aim of this study was to determine the effects of ifenprodil on the behavioral and electroencephalographic (EEG) manifestations of seizures in lindane-treated rats. Adult male Wistar rats with three electrodes implanted into the skull were treated intraperitoneally (i.p.) with lindane 8 mg/kg and observed for seizure behavior and EEG during the next 30 min. Seizure behavior was assessed by incidence, severity (determined by a descriptive rating scale ranging from 0 to 4) and duration of latency. Increasing doses of ifenprodil (5, 10, 20 mg/kg, i.p.) or vehicle were injected 30 min prior to lindane administration. Ifenprodil decreased the incidence and severity of lindane seizures and prolonged the latency to seizures in a dose-dependent manner. 20 mg/kg of ifenprodil significantly de- creased the incidence (p < 0.05) and severity (p < 0.05) of seizures when compared to the vehicle treatment. Latency to seizures was significantly prolonged by 10 and 20 mg/kg of ifenprodil. The estimated ED₅₀ value of ifenprodil was 15.53 (5.48–15.20) mg/kg. The lindane-induced bursts of spiking activity in EEG were not completely suppressed by the applied doses of ifenprodil. These results indicate that ifenprodil alleviates behavioral seizures and modifies EEG characteristics of lindane seizures in rats, thus showing the involvement of NMDA receptors containing the NR2B subunit in the mechanisms of lindane convulsions.

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Role of Gaba Receptor Complex in Low Dose Lindane (HCH) Induced Neurotoxicity: Neurobehavioural, Neurochemical and Electrophysiological Studies

Cited by 38 publications

References 18 publications

A Stable Chemical SUMO1–Ubc9 Conjugate Specifically Binds as a Thioester Mimic to the RanBP2–E3 Ligase Complex

A Stable Chemical SUMO1–Ubc9 Conjugate Specifically Binds as a Thioester Mimic to the RanBP2–E3 Ligase Complex

Fluorescent Transgenic Zebrafish Tg(nkx2.2a:mEGFP) Provides a Highly Sensitive Monitoring Tool for Neurotoxins

Influence of NR2B-Selective NMDA Antagonist on Lindane-Induced Seizures in Rats

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