Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.1.5 (neuropathy target esterase)
 1,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chlorpyrifos (diethyl 3,5,6-trichloro-2-pyridyl phosphorothionate) is a broad-spectrum organophosphorus (OP) insecticide. Anticipated increases in the already extensive use of this compound have prompted this reassessment of its neurotoxicity. Because chlorpyrifos and other OP insecticides are designed to produce acute cholinergic effects through inhibition of acetylcholinesterase (AChE) and some OP compounds can cause OP compound-induced delayed neurotoxicity (OPIDN) via chemical modification of neurotoxic esterase (neuropathy target esterase, NTE), this review focuses on the capacity of chlorpyrifos to precipitate these and other adverse neurological consequences. Chlorpyrifos exhibits only moderate acute toxicity in many mammalian species, due largely to detoxification of the active metabolite, chlorpyrifos oxon, by A-esterases. Rats given large doses of chlorpyrifos (sc in oil) have prolonged inhibition of brain AChE, possibly due to slow release of the parent compound from a depot. Associated cognitive and motor deficits return to normal well before recovery of AChE activity and muscarinic receptor down-regulation, as expected from classic tolerance. Controlled studies of OP compound exposures in humans also indicate that cognitive dysfunction requires substantial AChE inhibition. Information is relatively sparse on neurological dysfunction that is secondary to theoretical reproductive, developmental, or immunological effects, but the best available data indicate that such effects are unlikely to result from exposures to chlorpyrifos. In accord with the much greater inhibitory potency of chlorpyrifos oxon for AChE than for NTE, clinical reports and experimental studies indicate that OPIDN from acute exposures to chlorpyrifos requires doses well in excess of the LD50, even when followed by repeated doses of the OPIDN potentiator phenylmethanesulfonyl fluoride (PMSF). Likewise, studies in hens show that subchronic exposures at the maximum tolerated daily dose do not result in OPIDN. Although exposure to chlorpyrifos as a result of normal use is unlikely to produce classical OPIDN, a recent report stated that mild reversible sensory neuropathy had occurred in eight patients who had been exposed subchronically to unknown amounts of chlorpyrifos. It is not clear whether these cases represent an incorrect linkage of cause and effect, a newly disclosed reversible sensory component of OPIDN, or an entirely new phenomenon. The question of the potential for chlorpyrifos to cause this mild sensory neuropathy could be resolved by the use of quantitative tests of sensory function in animal experiments and/or prospective studies of humans with known exposures to chlorpyrifos.
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PMID:Assessment of the neurotoxic potential of chlorpyrifos relative to other organophosphorus compounds: a critical review of the literature. 753 75

These studies were intended to explore the relationship between autonomic neuropathy and erectile dysfunction (ED). Sensory thresholds reflecting the integrity of both large diameter, myelinated neurons (ie pressure, touch, vibration) and small diameter axons (ie hot and cold thermal sensation) were determined on the penis and finger. Data were compared across subjects with and without ED, controlling for age, hypertension and diabetes. The correlation of specific thresholds scores and IIEF values were also examined. Seventy-three patients who visited the academic urology clinics at Montefiore hospital were evaluated. All patients were required to complete the erectile function domain of the International Index of Erectile Function (IIEF) questionnaire: 20 subjects had no complaints of ED and scored within the 'normal' range on the IIEF. Patients were subsequently tested on their index finger and glans penis for vibration (Biothesiometer), pressure (Semmes-Weinstein monofilaments), spatial perception (Tactile Circumferential Discriminator), and warm and cold thermal thresholds (Physitemp NTE-2). Sensation of the glans penis, as defined by the examined sensory thresholds, was significantly diminished in patients with ED and these differences remained significant when controlling for age, diabetes and hypertension. In contrast, thresholds on the index finger were equivalent in the ED and non-ED groups. Threshold and IIEF scores were highly correlated, consistent with an association between diminished sensation and decreasing IIEF score (worse erectile functioning). These relations also remained significant when controlling for age, diabetes and hypertension. The findings demonstrate dysfunction of large and small diameter nerve fibers in patients with ED of all etiologies. Further, the neurophysiologic measures validate the use of the IIEF as an index of ED, as objective findings of sensory neuropathy were highly correlated with worse IIEF scores. The sensory threshold methods utilized represent novel, non-invasive and relatively simple procedures, which can be used in a longitudinal fashion to assess a patient's neurological response to therapies.
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PMID:The neuropathy of erectile dysfunction. 1249 74

Hereditary spastic paraplegia (HSP) is a syndrome designation describing inherited disorders in which lower extremity weakness and spasticity are the predominant symptoms. There are more than 50 genetic types of HSP. HSP affects individuals of diverse ethnic groups with prevalence estimates ranging from 1.2 to 9.6 per 100,000. Symptoms may begin at any age. Gait impairment that begins after childhood usually worsens very slowly over many years. Gait impairment that begins in infancy and early childhood may not worsen significantly. Postmortem studies consistently identify degeneration of corticospinal tract axons (maximal in the thoracic spinal cord) and degeneration of fasciculus gracilis fibers (maximal in the cervico-medullary region). HSP syndromes thus appear to involve motor-sensory axon degeneration affecting predominantly (but not exclusively) the distal ends of long central nervous system (CNS) axons. In general, proteins encoded by HSP genes have diverse functions including (1) axon transport (e.g. SPG30/KIF1A, SPG10/KIF5A and possibly SPG4/Spastin); (2) endoplasmic reticulum morphology (e.g. SPG3A/Atlastin, SPG4/Spastin, SPG12/reticulon 2, and SPG31/REEP1, all of which interact); (3) mitochondrial function (e.g. SPG13/chaperonin 60/heat-shock protein 60, SPG7/paraplegin; and mitochondrial ATP6); (4) myelin formation (e.g. SPG2/Proteolipid protein and SPG42/Connexin 47); (5) protein folding and ER-stress response (SPG6/NIPA1, SPG8/K1AA0196 (Strumpellin), SGP17/BSCL2 (Seipin), "mutilating sensory neuropathy with spastic paraplegia" owing to CcT5 mutation and presumably SPG18/ERLIN2); (6) corticospinal tract and other neurodevelopment (e.g. SPG1/L1 cell adhesion molecule and SPG22/thyroid transporter MCT8); (7) fatty acid and phospholipid metabolism (e.g. SPG28/DDHD1, SPG35/FA2H, SPG39/NTE, SPG54/DDHD2, and SPG56/CYP2U1); and (8) endosome membrane trafficking and vesicle formation (e.g. SPG47/AP4B1, SPG48/KIAA0415, SPG50/AP4M1, SPG51/AP4E, SPG52/AP4S1, and VSPG53/VPS37A). The availability of animal models (including bovine, murine, zebrafish, Drosophila, and C. elegans) for many types of HSP permits exploration of disease mechanisms and potential treatments. This review highlights emerging concepts of this large group of clinically similar disorders.
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PMID:Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. 2389 27