Disease relevance of Mme

• To determine whether deletion of NEP predisposes mice to uncontrolled inflammation, we compared dinitrobenzene sulfonic acid-induced colitis in wild-type and knockout mice [1].
• We examined whether neutral endopeptidase (NEP), a cell-surface enzyme that degrades SP in the extracellular fluid, terminates neurogenic inflammation in the colon [1].
• Neutral endopeptidase terminates substance P-induced inflammation in allergic contact dermatitis [2].
• The effector phase of allergic contact dermatitis (ACD) responses was examined in NEP(-/-) knockout and NEP(+/+) wild-type mice and compared with the irritant contact dermatitis response in these animals [2].
• Conversely, pretreatment of wild-type mice with the NEP inhibitor phosphoramidon exacerbated enteritis [3].

Psychiatry related information on Mme

• These studies provide the impetus for further investigating of the use of NEP in a gene transfer therapy paradigm to prevent the accumulation of Abeta and prevent or delay the onset of Alzheimer's disease [4].
• Neutral endopeptidase and alcohol consumption, experiments in neutral endopeptidase-deficient mice [5].
• NEP knockouts developed normally, but showed enhanced aggressive behaviour in the resident-intruder paradigm, and altered locomotor activity as assessed in the photobeam system [6].
• The effect of the inhibition of aminopeptidase and enkephalinase A on the pain threshold of mice and rats was investigated, using bestatin and thiorphan as selective peptidase inhibitors [7].
• Enhancement of enkephalin activity with the enkephalinase inhibitor, SCH 34826, significantly reduced task performance by male deer mice [8].

High impact information on Mme

• The enzymatic activity of an Abeta-degrading endopeptidase, neprilysin, is elevated in the brains of "enriched" mice and inversely correlated with amyloid burden [9].
• Among various effector candidates, only somatostatin upregulated neprilysin activity in primary cortical neurons [10].
• The control of microvascular permeability and blood pressure by neutral endopeptidase [11].
• Thus, absence of NEP may predispose development of inflammation and hypotension [11].
• Such a role is further supported by the ontogenetic development of enkephalinase, its substrate specificity accounting for the increased biological activity of several enkephalin analogues and its adaptive increase following chronic treatment with morphine [12].

Chemical compound and disease context of Mme

• Neutral endopeptidase (EC 3.4.24.11) terminates colitis by degrading substance P [1].
• Neutral endopeptidase knockout induces hyperalgesia in a model of visceral pain, an effect related to bradykinin and nitric oxide [13].
• In vitro the two compounds inhibit both ACE and enkephalinase activities with similar, nanomolar potencies, and in vivo, glycopril and alatriopril, the corresponding diester prodrugs, occupy the two enzyme molecules in lung at similar low dosages (0.2-0.5 mg/kg of body weight, per os) [14].
• Tumor-suppressive effects of neutral endopeptidase in androgen-independent prostate cancer cells [15].
• We compared susceptibility to Candida vaginitis in derived murine substrains differing in sensitivity to estrogen (CD-1 and CD10, resistant; CD3 and C57BL/6 responsive), and in F1 crosses [16].

Biological context of Mme

• Because we have previously shown that intestinal inflammation results in down-regulation of NEP and diminished degradation of SP, our present results suggest that defects in NEP expression contribute to uncontrolled inflammation [1].
• In NEP knockout mice, the SP concentration in the colon was approximately 2.5-fold higher than in wild-type mice, suggesting increased bioavailability of SP [1].
• The use of NEP antagonists as candidate drugs in cardiovascular disease is suggested by the blood pressure data reported herein [11].
• Neprilysin-sensitive synapse-associated amyloid-beta peptide oligomers impair neuronal plasticity and cognitive function [17].
• Finally, we show that NCT expression peaked 24 h after NCT cDNA transfection of wild-type and NCT-/- fibroblasts, while neprilysin expression drastically increased only after 36 h and was maximal at 48 h [18].

Anatomical context of Mme

• Thus, NEP maintains low levels of SP in the extracellular fluid under basal conditions and terminates its proinflammatory effects [1].
• (2) In developing tooth germ and mammary gland; mRNA encoding the neutral endopeptidase (NEP) that degrades secreted tachykinins is spatially and temporally co-expressed with tachykinin precursor mRNA [19].
• The ACD ear swelling response was 2.5-fold higher in animals lacking NEP and was accompanied by a significant increase in plasma extravasation and infiltration of inflammatory leukocytes [2].
• NEP was found to be normally immunolocalized in epidermal keratinocytes and dermal blood vessels [2].
• The aim of this study was to analyze the function and expression of tachykinins, tachykinin receptors, and neprilysin (NEP) in the mouse uterus [20].

Associations of Mme with chemical compounds

• The exacerbated inflammation in knockout mice was prevented by recombinant NEP and SR140333 [1].
• The cell surface metalloprotease neutral endopeptidase (NEP) is the principal proteolytic substance P-degrading enzyme [2].
• The augmented ACD response in NEP(-/-) animals was abrogated by either administration of a neurokinin receptor 1 antagonist or by repeated pretreatment with topical capsaicin [2].
• 3. Pretreatment with captopril (2.5 mg kg(-1), i.v.), a selective inhibitor of angiotensin converting enzyme (ACE), either alone or in combination with phosphoramidon (2.5 mg kg(-1), i.v.), a selective inhibitor of neutral endopeptidase (NEP), increased baseline leakage of Evans blue in the absence of any exogenous inflammatory mediator [21].
• Racecadotril, which is rapidly metabolized to its active metabolite thiorphan, is a neutral endopeptidase (NEP) inhibitor used in clinical practice for diarrhoea with a remarkable safety profile [22].

Enzymatic interactions of Mme

• D. melanogaster NEP2 also differs from human NEP in the manner in which the peptidase cleaves the tachykinin, GPSGFYGVR-amide [23].

Regulatory relationships of Mme

• Neprilysin regulates amyloid Beta peptide levels [4].
• We recently demonstrated that the presenilin-dependent gamma-secretase complex regulates the expression and activity of neprilysin, one of the main enzymes that degrade the amyloid beta-peptide (Abeta) which accumulates in Alzheimer's disease [18].
• These data suggest that endothelin-1 contributes to the pathogenesis of chagasic cardiomyopathy and interventions that inhibit the synthesis of endothelin-1 and/or neutral endopeptidase might have a protective effect on myocardial structure and function in murine Chagas' disease [24].
• Actinonin which has been found to be an inhibitor of aminopeptidase M (EC 3.4.11.2) also inhibited enkephalinase A (EC 3.4.24.11) and enkephalin aminopeptidase which were partially purified from the corpus striatum membrane of guinea-pig brain [25].

Other interactions of Mme

• However, the mRNAs of PPT-B, PPT-C and NEP appeared in blastocyst-stage embryos [26].
• We have investigated the use of NEP as a potential therapeutic agent to prevent the accumulation of Abeta peptides in the brain [4].
• Conversely, genetic deletion of NEP significantly worsened survival (0% vs 90% at 120 hours, P <.001) and exacerbated pancreatic MPO and pancreatitis-associated lung injury [27].
• We determined whether genetic deletion of the NK1-R reduces mortality and, conversely, whether genetic deletion of NEP increases mortality in a lethal model of hemorrhagic pancreatitis [27].
• Here, we examined the influence of endogenous nicastrin (NCT), a member of the gamma-secretase complex, on neprilysin physiology [18].

Analytical, diagnostic and therapeutic context of Mme

• NEP and ECEL1/DINE mRNA levels were higher in Hyp cells than in normal cells, and in situ hybridization of ECEL1/DINE confirmed higher levels of expression in the Hyp mouse than in normal cells [28].
• Ventilatory responses to acute hypoxia were measured by indirect plethysmography in unanesthetized, unrestrained wild-type mice and in mice in which the NEP gene was deleted (NEP -/-) [29].
• RESULTS: In NEP(+/+) mice, intraperitoneal injection of porcine pancreatic elastase (elastase, 0.085 U/g at t = 0 h and t = 1 h) caused a 7-fold increase in lung myeloperoxidase (MPO) activity and marked pulmonary edema, neutrophil infiltration, and hemorrhage at 4 h as compared to control animals [30].
• In addition, lymphoid cells in both (rIL-7) independent and rIL-7-dependent in vitro pro-B cell cultures lack CD10 expression [31].
• A pharmacological blockade of NEP-activity enhances extracellular enkephalin concentrations and induces opioid-dependent analgesia [6].

References