Carrasco M

References (8)

Title : Poster: Cembranoids structureactivity relationship for protection against diisopropylfluorophosphate damage -
Author(s) : Eterovic VA , Carrasco M , Perez D , Ebrahim HY , Ferchmin PA , El Sayed KA
Ref : Biochemical Pharmacology , 97 :627 , 2015
PubMedID:

Title : Neuroprotection Against Diisopropylfluorophosphate in Acute Hippocampal Slices - Ferchmin_2015_Neurochem.Res_40_2143
Author(s) : Ferchmin PA , Perez D , Cuadrado BL , Carrasco M , Martins AH , Eterovic VA
Ref : Neurochem Res , 40 :2143 , 2015
Abstract : Diisopropylfluorophosphate (DFP) is an irreversible inhibitor of acetylcholine esterase 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 nine 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.
ESTHER : Ferchmin_2015_Neurochem.Res_40_2143
PubMedSearch : Ferchmin_2015_Neurochem.Res_40_2143
PubMedID: 26438150

Title : 4R-cembranoid protects against diisopropylfluorophosphate-mediated neurodegeneration - Ferchmin_2014_Neurotoxicol_44C_80
Author(s) : Ferchmin PA , Andino M , Reyes Salaman R , Alves J , Velez-Roman J , Cuadrado B , Carrasco M , Torres-Rivera W , Segarra A , Martins AH , Lee JE , Eterovic VA
Ref : Neurotoxicology , 44C :80 , 2014
Abstract : Many organophosphorous esters synthesized for applications in industry, agriculture, or warfare irreversibly inhibit acetylcholinesterase, and acute poisoning with these compounds causes life-threatening cholinergic overstimulation. Following classical emergency treatment with atropine, an oxime, and a benzodiazepine, surviving victims often suffer brain neurodegeneration. Currently, there is no pharmacological treatment to prevent this brain injury. Here we show that a cyclic diterpenoid, (1S,2E,4R,6R,7E,11E)-cembra-2,7,11-triene-4,6-diol (4R) ameliorates the damage caused by diisopropylfluorophosphate (DFP) in the hippocampal area CA1. DFP has been frequently used as a surrogate for the warfare nerve agent sarin. In rats, DFP is lethal at the dose used to cause brain damage. Therefore, to observe brain damage in survivors, the death rate was reduced by pre-administration of the peripherally acting antidotes pyridostigmine and methyl atropine or its analog ipratropium. Pyridostigmine bromide, methyl atropine nitrate, and ipratropium bromide were dissolved in saline and injected intramuscularly at 0.1mg/kg, 20mg/kg, and 23mg/kg, respectively. DFP (9mg/kg) dissolved in cold water was injected intraperitoneally. 4R (6mg/kg) dissolved in DMSO was injected subcutaneously, either 1h before or 5 or 24h after DFP. Neurodegeneration was assessed with Fluoro-Jade B and amino cupric silver staining; neuroinflammation was measured by the expression of nestin, a marker of activated astrocytes. Forty-eight hours after DFP administration, 4R decreased the number of dead neurons by half when injected before or after DFP. 4R also significantly decreased the number of activated astrocytes. These data suggest that 4R is a promising new drug that could change the therapeutic paradigm for acute poisoning with organophosphorous compounds by the implementation of a second-stage intervention after the classical countermeasure treatment.
ESTHER : Ferchmin_2014_Neurotoxicol_44C_80
PubMedSearch : Ferchmin_2014_Neurotoxicol_44C_80
PubMedID: 24928201

Title : Poster: Protective activity of (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol analogues against diisopropylfluorophosphate neurotoxicity -
Author(s) : Eterovic VA , Del Valle-Rodrigez A , Perez D , Carrasco M , Khanfar MA , El Sayed KA , Ferchmin PA
Ref : Biochemical Pharmacology , 86 :1233 , 2013
PubMedID:

Title : Kinin-B2 receptor exerted neuroprotection after diisopropylfluorophosphate-induced neuronal damage - Torres-Rivera_2013_Neurosci_247C_273
Author(s) : Torres-Rivera W , Perez D , Park KY , Carrasco M , Platt MO , Eterovic VA , Ferchmin PA , Ulrich H , Martins AH
Ref : Neuroscience , 247C :273 , 2013
Abstract : The kinin-B2 receptor (B2BKR) activated by its endogenous ligand bradykinin participates in various metabolic processes including the control of arterial pressure and inflammation. Recently, functions for this receptor in brain development and protection against glutamate-provoked excitotoxicity have been proposed. Here, we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model. Following slice perfusion for 10min with diisopropylfluorophosphate (DFP) to initiate the noxious stimulus, responses of pyramidal neurons upon an electric impulse were reduced to less than 30% of control amplitudes. Effects on synaptic-elicited population spikes were reverted when preparations had been exposed to bradykinin 30min after challenging with DFP. Accordingly, bradykinin-induced population spike recovery was abolished by HOE-140, a B2BKR antagonist. However, the kinin-B1 receptor (B1BKR) agonist Lys-des-Arg9-bradykinin, inducing the phosphorylation of mitogen-activated protein kinase (MEK/MAPK) and cell death, abolished bradykinin-mediated neuroprotection, an effect, which was reverted by the ERK inhibitor PD98059. In agreement with pivotal B1BKR functions in this process, antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity. On the other hand pralidoxime, an oxime, reactivating acetylcholinesterase (AChE) after organophosphate poisoning, induced population spike recovery after DFP exposure in the presence of bradykinin and Lys-des-Arg9-bradykinin. Lys-des-Arg9-bradykinin did not revert protection exerted by pralidoxime, however when instead bradykinin and Ly-des-Arg9-bradykinin were superfused together, recovery of population spikes diminished. These findings again confirm the neuroprotective feature of bradykinin, which is, diminished by its endogenous metabolites, stimulating the B1BKR, providing a novel understanding of the physiological roles of these receptors.
ESTHER : Torres-Rivera_2013_Neurosci_247C_273
PubMedSearch : Torres-Rivera_2013_Neurosci_247C_273
PubMedID: 23735753

Title : Poster: 4R-cembratrienediol protects against diisopropylfluorophosphate-induced neurodegeneration with a long window of therapeutic opportunity -
Author(s) : Ferchmin PA , Alves JM , Perez D , Cuadrado B , Carrasco M , Roman JMV , Martins HAB , Segarra AC , Eterovic VA
Ref : Biochemical Pharmacology , 82 :1045 , 2011
PubMedID:

Title : A cembranoid protects acute hippocampal slices against paraoxon neurotoxicity - Eterovic_2011_Toxicol.In.Vitro_25_1468
Author(s) : Eterovic VA , Perez D , Martins AH , Cuadrado BL , Carrasco M , Ferchmin PA
Ref : Toxicol In Vitro , 25 :1468 , 2011
Abstract : Many neurotoxic organophosphates (OPs) inhibit acetylcholinesterase (AChE) and as a result can cause a life threatening cholinergic crisis. Current medical countermeasures, which typically include atropine and oximes target the cholinergic crisis and are effective in decreasing mortality but do not sufficiently protect against delayed neurological deficits. There is, therefore, a need to develop neuroprotective drugs to prevent long-term neurological deficits. We used acute hippocampal slices to test the hypothesis that 4R,6R-cembratrienediol (4R) protects against functional damage caused by the OP paraoxon (POX). To assess hippocampal function, we measured synaptically evoked population spikes (PSs). Application of 4R reversed POX inhibition of PSs and the EC(50) of this effect was 0.8 muM. Atropine alone did not protect against POX neurotoxicity, but it did enhance protection by 4R. Pralidoxime partially regenerated AChE activity and protected against POX inhibition of PSs. 4R did not regenerate AChE suggesting that under our experimental conditions, the deleterious effect of POX on hippocampal function is not directly related to AChE inhibition. In conclusion, 4R is a promising neuroprotective compound against OP neurotoxins.
ESTHER : Eterovic_2011_Toxicol.In.Vitro_25_1468
PubMedSearch : Eterovic_2011_Toxicol.In.Vitro_25_1468
PubMedID: 21569834

Title : Poster: A novel nicotinic antagonist protects the function of hippocampal slices against neurotoxic organophosphates -
Author(s) : Ferchmin PA , Perez D , Martins AH , Cuadrado BL , Carrasco M , Eterovic VA
Ref : Biochemical Pharmacology , 78 :904 , 2009
PubMedID: