Mundy WR

References (5)

Title : Advancing the science of developmental neurotoxicity (DNT): testing for better safety evaluation -
Author(s) : Bal-Price AK , Coecke S , Costa L , Crofton KM , Fritsche E , Goldberg A , Grandjean P , Lein PJ , Li A , Lucchini R , Mundy WR , Padilla S , Persico AM , Seiler AE , Kreysa J
Ref : ALTEX , 29 :202 , 2012
PubMedID: 22892558

Title : Time course of changes in cholinergic and neurotrophin-related markers after infusion of colchicine into the basal forebrain - Shaughnessy_1998_Brain.Res_781_61
Author(s) : Shaughnessy LW , Mundy WR , Tilson HA , Barone S, Jr.
Ref : Brain Research , 781 :61 , 1998
Abstract : After bilateral infusions of colchicine or vehicle in the rat nucleus basalis magnocellularis, the time course of changes in several cholinergic and neurotrophin-related markers were assessed. Animals were sacrificed at 3, 7, 14, 28, 35 and 84 days post-lesion, and both the NBM and cortical areas were assessed. Sections were stained immunohistochemically for choline acetyltransferase (ChAT) or p140trk (trk) or histochemically for acetylcholinesterase (AChE). ChAT activity and neurotrophin protein levels were assessed regionally. The number of ChAT immunoreactive NBM neuronal profiles decreased beginning 3 days post-lesion and reach maximal loss by 28 days post-lesion, with no recovery. Examination of trk-IR around the NBM revealed a time-dependent decrease in trk-IR of magnocellular neuron and an increase in trk-IR of astrocytes at 14 and 28 days post-lesion. The density of AChE-stained cortical fibers was maximally decreased 3 days post-lesion followed by an increase in fiber staining across the remaining time points. Cortical ChAT activity showed the largest decrease at 7 days followed by recovery 84 days after colchicine infusion. There was an increase in NGF in the parietal cortex after colchicine infusion but no change in BDNF level. These patterns of changes in the cholinergic and neurotrophin-related markers suggest an association between NGF and lesion-induced compensatory responses in the basal forebrain cholinergic system.
ESTHER : Shaughnessy_1998_Brain.Res_781_61
PubMedSearch : Shaughnessy_1998_Brain.Res_781_61
PubMedID: 9507066

Title : Inhibition of rat brain phosphatidylinositol-specific phospholipase C by aluminum: regional differences, interactions with aluminum salts, and mechanisms - Nostrandt_1996_Toxicol.Appl.Pharmacol_136_118
Author(s) : Nostrandt AC , Shafer TJ , Mundy WR , Padilla S
Ref : Toxicol Appl Pharmacol , 136 :118 , 1996
Abstract : We have shown previously that aluminum chloride (AlCl3, 10-500 microM) inhibits hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by phosphatidylinositol-specific phospholipase C (PI-PLC) in a concentration-dependent manner. In the present study, we characterize further the effects of aluminum on PI-PLC. A comparison of different brain regions and liver revealed varying basal PI-PLC specific activities, as well as differential susceptibility to inhibition by 100 microM AlCl3. The hippocampus had the highest specific activity of PI-PLC, followed by striatum, frontal cortex, cerebellum, and liver. PI-PLC inhibition by 100 microM AlCl3 was greatest in the liver, followed by cerebellum, hippocampus, cortex, and striatum. Moreover, 100 microM AlCl3 or aluminum lactate (Al (lac)) were similarly effective at inhibiting PI-PLC activity in rat cortical tissue. Addition of AlCl3 (100 microM) decreased PI-PLC activity at CaCl2 concentrations ranging from 0 to 2 mM; however, AlCl3 did not affect the shape of the calcium concentration curve, suggesting that aluminum does not inhibit PI-PLC activity by interference with the cofactor, calcium. AlCl3 (100 microM) did inhibit rat cortical PI-PLC hydrolysis of PIP2 in a competitive manner. These results demonstrate some regional/tissue differences in PI-PLC activity and its sensitivity to aluminum, and effects of AlCl3 and Al(lac) consistent with the effects previously noted in PI turnover in brain slices. Furthermore, our results suggest that competitive inhibition of PLC-mediated PIP2 hydrolysis by aluminum is a potential mechanism by which aluminum may cause the disruptions phosphoinositide signaling which have been reported following in vivo and in vitro exposure.
ESTHER : Nostrandt_1996_Toxicol.Appl.Pharmacol_136_118
PubMedSearch : Nostrandt_1996_Toxicol.Appl.Pharmacol_136_118
PubMedID: 8560464

Title : Time-dependent effects of acute chlorpyrifos administration on spatial delayed alternation and cholinergic neurochemistry in weanling rats - Stanton_1994_Neurotoxicol_15_201
Author(s) : Stanton ME , Mundy WR , Ward T , Dulchinos V , Barry CC
Ref : Neurotoxicology , 15 :201 , 1994
Abstract : On postnatal day 21 (PND21), Long-Evans rat pups received a single subcutaneous injection of either 0 (corn oil vehicle), 90, 120, or 240 mg/kg chlorpyrifos and were then tested for T-maze delayed alternation on PND23 or 26. Acetylcholinesterase (AChE) activity and muscaranic receptor density [i.e., quinuclidinyl benzilate (QNB) binding] were determined in hippocampus and cortex of brains taken from pups 15 hours after the end of behavioral testing (i.e., the morning of PND24, and 27). Pups exposed to the 240 mg/kg dose of chlorpyrifos showed signs of overt toxicity that precluded behavioral testing. Exposure to the 120 mg/kg dose produced a selective memory impairment (ie., a deficit in delayed alternation but not position discrimination) relative to the 90 mg/kg and vehicle groups. This impairment was transient, however, as it appeared on PND23 and was absent by PND26. PND21 exposure to chlorpyrifos produced dose-related inhibition and recovery of brain AChE over the PND24-27 age range. A similar pattern was observed in hippocampus. Binding of [3H]QNB was reduced in frontal cortex on PND27 only at the 240 mg/kg dose. No significant effects were observed in the hippocampus. These results suggest that the neurochemical effects of acute chlorpyrifos administration are more transient, and the behavioral effects are smaller and shorter-lived than what has been reported in adult rats.
ESTHER : Stanton_1994_Neurotoxicol_15_201
PubMedSearch : Stanton_1994_Neurotoxicol_15_201
PubMedID: 7522308

Title : Correlation of the anticholinesterase activity of a series of organophosphates with their ability to compete with agonist binding to muscarinic receptors - Ward_1993_Toxicol.Appl.Pharmacol_122_300
Author(s) : Ward TR , Ferris DJ , Tilson HA , Mundy WR
Ref : Toxicology & Applied Pharmacology , 122 :300 , 1993
Abstract : Some compounds that inhibit acetylcholinesterase (AChE) activity compete directly with quinuclidinyl benzilate (QNB) binding, a muscarinic antagonist which binds to all subtypes equally, and with cis-methyldioxolane (CD), an agonist that binds with high affinity to the M2 subtype of muscarinic receptors. The relationship between inhibition of AChE activity and the capability to affect muscarinic receptors directly has not been systematically explored. The interaction of eight organophosphates with muscarinic receptors was compared to their ability to inhibit AChE activity in vitro in tissue homogenates from rat hippocampus and frontal cortex, two cholinergically enriched areas of the brain. Of the compounds tested only echothiophate competed for [3H]QNB binding and only at concentrations greater than 100 microM. The anticholinesterase compounds were also tested for their ability to compete with a muscarinic receptor agonist, [3H]CD, which binds with high affinity (approximate KD = 3.5 nM) to 10 and 3% of the muscarinic receptors in the frontal cortex and hippocampus, respectively. The anticholinesterase compounds inhibited high-affinity [3H]CD binding up to 80% and the effects were similar in both tissues. Echothiophate and DFP were potent inhibitors of [3H]CD binding, as were the active "oxon" forms of parathion, malathion, and disulfoton. The parent "thio" forms of these insecticides, however, were much less effective in competing for [3H]CD binding. A similar pattern of potency was observed for the inhibition of brain AChE activity. A strong correlation was found between the ability of a compound to inhibit AChE activity and the ability to compete with [3H]CD binding. These data suggest that the biological effects of cholinesterase-inhibiting compounds may be due to more than their ability to inhibit AChE.
ESTHER : Ward_1993_Toxicol.Appl.Pharmacol_122_300
PubMedSearch : Ward_1993_Toxicol.Appl.Pharmacol_122_300
PubMedID: 8212012