A novel nicotinic antagonist protects the function of hippocampal slices against neurotoxic organophosphates

Ferchmin, P.A.; Pérez, Dinely; Martins, Ana; Cuadrado, Brenda L.; Carrasco, Marimée; Eterović, Vesna A.

doi:10.1016/j.bcp.2009.06.043

Cited by 2 publications

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“…As mentioned in the introduction, the neurotoxicity and neuroprotection observed in slices is a good predictor of the result in vivo. In the present case, the neuroprotection by 4R, first observed in slices [32], was reproduced in vivo [14]. A puzzling finding is the very early onset of the caspase-dependent neurotoxic effect, which is most likely apoptosis.…”

Section: Discussionmentioning

confidence: 52%

“…The quaternary structure of pralidoxime and other AChE reactivators limit their penetration through the intact BBB. However, there are proofs of central reactivation of AChE [31] and it was demonstrated that pralidoxime penetrates the blood-brain barrier [32]. The accepted clinical application and mechanism of the action of oximes, including pralidoxime, is a reactivation of AChE inhibited by OPs before the aging of the OP-AChE complex is completed.…”

Section: Discussionmentioning

confidence: 99%

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Neuroprotection Against Diisopropylfluorophosphate in Acute Hippocampal Slices

et al. 2015

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Diisopropylfluorophosphate (DFP) is an irreversible inhibitor of acetylcholine esterase (AChE) and a surrogate of the organophosphorus (OP) nerve agent sarin. The neurotoxicity of DFP was assessed as a reduction of population spike (PS) area elicited by synaptic stimulation in acute hippocampal slices. Two classical antidotes, atropine, and pralidoxime, and two novel antidotes, 4R-cembranotriene-diol (4R) and a caspase 9 inhibitor, were tested. Atropine, pralidoxime, and 4R significantly protected when applied 30 min after DFP. The caspase inhibitor was neuroprotective when applied 5–10 min before or after DFP, suggesting that early synaptic apoptosis is responsible for the loss of PSs. It is likely that apoptosis starts at the synapses and, if antidotes are not applied, descends to the cell bodies, causing death. The acute slice is a reliable tool for mechanistic studies, and the assessment of neurotoxicity and neuroprotection with PS areas is, in general, pharmacologically congruent with in vivo results and predicts the effect of drugs in vivo. 4R was first found to be neuroprotective in slices and later we demonstrated that 4R is neuroprotective in vivo. The mechanism of neurotoxicity of OPs is not well understood, and there is a need for novel antidotes that could be discovered using acute slices.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Neuroprotection Against Diisopropylfluorophosphate in Acute Hippocampal Slices

et al. 2015

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“…6,7,11-14 In the acute hippocampal slice preparation, 1 rescues the PSs from NMDA-induced damage, 7,12 as well as from two neurotoxic OPs: paraoxon 6 and DFP. 13 All three toxic stimuli, NMDA, paraoxon and DFP, decreased the PS area in a concentration and time-dependent manner while post-application of 1 reversed the toxic effect. Cembranoid 1 rescued the PS by triggering an antiapoptotic mechanism through noncompetitive inhibition of the α7 nicotinic acetylcholine receptor (α7); inhibition of the α7 receptor indirectly caused the activation of Akt/PKB in pyramidal neurons.…”

Section: Introductionmentioning

confidence: 90%

Protective activity of (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol analogues against diisopropylfluorophosphate neurotoxicity: Preliminary structure–activity relationship and pharmacophore modeling

Eterović

Valle-Rodriguez

Pérez

et al. 2013

Bioorganic & Medicinal Chemistry

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Diisopropylfluorophosphate (DFP) is an organophosphorous insecticide used as a surrogate for the more toxic chemical warfare nerve agent sarin. DFP produces neurotoxicity in vivo and irreversibly decreases the area of population spikes recorded from the CA1 region of acute hippocampal slices. (1S,2E,4R,6R,7E,11E)-2,7,11-Cembratriene-4,6-diol (1) is a neuroprotective natural cembranoid that reverses DFP-induced damage both in vivo and in the hippocampal slice. Cembranoid 1 acts by noncompetitive inhibition of the α7 nicotinic acetylcholine receptor. This study aims at establishing a preliminary structure-activity relationship to define the neuroprotective cembranoid pharmacophores using the hippocampal slice assay and pharmacophore modeling. Fourteen natural, semisyntheti or biocatalytic cembranoid analogues 2-15 related to 1 were tested for their capacity to protect the population spikes from DFP-induced damage and intrinsic toxicity. Twelve cembranoids caused significant reversal of DFP toxicity; only 3 active analogues displayed minor intrinsic toxicity at 10 μM. The C-4 epimer of 1 (2) and the 4-O-methyl ether analogue of 1 (3), were totally devoid of neuroprotective activity. The results suggested a model for cembranoid binding where the hydrophobic ring surface binds to a hydrophobic (Hbic) patch on the receptor molecule and an electronegative atom (oxygen or sulfur) in proper spatial relationship to the ring surface interacts with an electropositive group in the receptor binding site. A pharmacophore model consisting of 1 hydrogen bond acceptor (HBA), 2 Hbic, and 10 exclusion spheres was established using HipHop-REFINE and supported the above mentioned pharmacophoric hypothesis.

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A novel nicotinic antagonist protects the function of hippocampal slices against neurotoxic organophosphates

Cited by 2 publications

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Neuroprotection Against Diisopropylfluorophosphate in Acute Hippocampal Slices

Neuroprotection Against Diisopropylfluorophosphate in Acute Hippocampal Slices

Protective activity of (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol analogues against diisopropylfluorophosphate neurotoxicity: Preliminary structure–activity relationship and pharmacophore modeling

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