Safety and feasibility of a telemonitoring-guided exercise program in patients receiving cardiac resynchronization therapy.

BACKGROUND: Telerehabilitation is an alternative clinic-based rehabilitation. A remote monitoring (RM) system attached to a cardiac rhythm device can collect physiological data and the device function. This study aimed to evaluate the safety and feasibility of telerehabilitation supervised by an RM in patients receiving cardiac resynchronization therapy (CRT). METHODS: A single group pre-post exercise program was implemented for 3 months in 18 CRT recipients. The exercise regimen consisted of walking a prescribed number of steps based on a 6-min walk distance (6MWD) achieved at baseline. The patients were asked to exercise 3 to 5 times per week for up to 30 min per session, wearing an accelerometer to document the number of steps taken. The safety was assessed by the heart failure hospitalizations and all-cause death. The feasibility was measured by the improvement in the quality of life (QOL) using the EuroQol 5 dimensions, and daily active time measured by the CRT, 6MWD, B-type natriuretic peptide (BNP) level, and left ventricular ejection fraction (LVEF). RESULTS: No patients had heart failure hospitalizations or died. No patients had any ventricular tachyarrhythmias. One patient needed to suspend the exercise due to signs of exacerbated heart failure by the RM. Compared to baseline, there were significant improvements in the QOL (-0.037, p < .05), active time (1.12%/day, p < .05), and 6MWD (11 m, p < .001), but not the BNP (-32.4 pg/ml, p = .07) or LVEF (0.28%, p = .55). CONCLUSIONS: Three months of RM-guided walking exercise in patients with CRT significantly increased the QOL, active time, and exercise capacity without any adverse effects.

Atmospheric response to high-resolution topographical and radiative forcings in a general circulation model of Venus: Time-mean structures of waves and variances.

Thermal tides, stationary waves, and general circulation are investigated using a T63 Venus general circulation model (GCM) with solar and thermal radiative transfer in the presence of high-resolution surface topography, based on time average analysis. The simulated wind and static stability are very similar to the observed ones (e.g., Horinouchi et al., 2018; Ando et al., 2020). The simulated thermal tides accelerate an equatorial superrotational flow with a speed of ~90 m s-1 around the cloud-heating maximum (~65 km). The zonal-flow acceleration rates of 0.2-0.5 m s-1 Earth day-1 are produced by both horizontal and vertical momentum fluxes at low latitudes. In the GCM simulation, strong solar heating above the cloud top (>69 km) and infrared heating around the cloud bottom (~50 km) modify the vertical structures of thermal tides and their vertical momentum fluxes, which accelerate zonal flow at 103 Pa (~75 km) and 104 Pa (~65 km) at the equator and around 103 Pa at high latitudes. Below and in the cloud layer, surface topography weakens the zonal-mean zonal flow over the Aphrodite Terra and Maxwell Montes, whereas it enhances the zonal flow in the southern polar region. The high-resolution topography produces stationary fine-scale bow structures at the cloud top and locally modifies the variances in the geographical coordinates (i.e., the activity of unsteady wave components). Over the high mountains, vertical spikes of the vertical wind variance are found, indicating penetrative plumes and gravity waves. Negative momentum flux is also locally enhanced at the cloud top over the equatorial high mountains. In the solar-fixed coordinate system, the variances (i.e., the activity of waves other than thermal tides) of flow are relatively higher on the nightside than on the dayside at the cloud top. Strong dependences of the eddy heat and momentum fluxes on local time are predominant. The local-time variation of the vertical eddy momentum flux is produced by both thermal tides and solar-related, small-scale gravity waves.

A Decision Tree-Based Survival Analysis of Patients with a History of Inappropriate Implantable Cardioverter-Defibrillator Therapy.

Implantable cardioverter-defibrillators (ICDs) improve survival in patients who are at risk of sudden death. However, inappropriate therapy is commonly given to ICD recipients, and this situation may be associated with an increased risk of death. This study aimed to construct a risk stratification scheme by using decision tree analysis in patients who received inappropriate ICD therapy.Mortality was calculated from a retrospective data analysis of a multicenter cohort involving 417 ICD recipients. Inappropriate therapy was defined as therapy for nonventricular arrhythmias, including sinus tachycardia, supraventricular tachycardia, atrial fibrillation/flutter, oversensing, and lead failure. Inappropriate therapy included antitachycardia pacing, cardioversion, and defibrillation. The prognostic factors were identified by a Cox proportional hazards regression analysis, and we constructed a decision tree.During an average follow-up of 5.2 years, 48 patients (12%) had all-cause death. A multivariate Cox hazard model revealed that the age (hazard ratio [HR] 1.06, P < 0.001), ln B-type natriuretic peptide (BNP) (HR 1.47, P = 0.02), nonsinus rhythm at implantation (HR 2.70, P < 0.05), and inappropriate therapy occurring during sedentary/awake conditions (HR 3.51, P = 0.001) correlated with an increased risk of mortality. An inappropriate therapy due to abnormal sensing (HR 0.16, P = 0.04) decreased the risk of mortality. Furthermore, a decision tree analysis stratified the patients well by using 4 covariates: BNP, activity at the time of inappropriate therapy, mechanism of inappropriate therapy, and baseline rhythm at ICD implantation (log-rank test, P < 0.0001).We identified the predictors of mortality in inappropriate ICD therapy recipients and constructed a risk stratification scheme by using decision tree analysis.

Taxonomic information on some Japanese Chironomidae (Diptera) described by Dr. M. Sasa (†).

Holotypes of 19 species and non-type specimens preserved in the Sasa collection at The National Museum of Science, Tokyo, Japan, have been examined. Seventeen new synonyms are given, as follows: Paratrissocladius ogasaduodecimus Sasa et Suzuki, 1997 = Paraphaenocladius impensus (Walker, 1856); Bryophaenocladius togafelix Sasa et Okazawa, 1992, and B. toganitemus Sasa et Okazawa, 1992 = Pseudorthocladius togakileus Sasa et Okazawa, 1992; Bryophaenocladius togatenuis Sasa et Okazawa, 1992 of Smittia nudipennis (Goetghebuer, 1913); Chironomus daitoefeus Sasa et Suzuki, 2001 of C. circumdatus Kieffer, 1916; C. inaabeus Sasa, Kitami et Suzuki, 2001 = C. nippodorsalis Sasa, 1979; C. tokarabeceus Sasa et Suzuki, 1995 = C. okinawanus Hasegawa et Sasa, 1987; C. ginzanbeceus Sasa et Suzuki, 2001 = C. riparius Meigen, 1904; C. simantobeceus Sasa , Suzuki et Sakai, 1998 = C. claggi Tokunaga, 1964; C. echizensis Sasa, 1994 = C. yoshimatsui Martin et Sublette, 1972; Chironomus famiabeus Sasa, 1996, C. inabeceus Sasa, Kitami et Suzuki, 2001 and C. ginzanabeus Sasa et Suzuki, 2001 = Glyptotendipes biwasecundus Sasa et Kawai, 1987; Chironomus kagaensis Sasa, 1994 = Glyptotendipes tokunagai Sasa, 1979; Chironomus toyamabiceus Sasa, 1996 = Kiefferulus umbraticola Yamamoto, 1979; Microtendipes iriocedeus Sasa et Suzuki, 2000 of Polypedilum bingoparadoxum Kawai, Inoue et Imabayashi , 1998. The sufficient reason why Chironomus daitocedeus Sasa et Suzuki, 2001 should be treated as a junior synonym of C. javanus Kieffer, 1924 is shown. Two further species: Paratrissocladius sudagaicedeus Sasa et Tanaka, 2001 and Bryophaenocladius togatenellus Sasa et Okazawa, 1992 are transferred to Chaetocladius. Specimens from Okinawa, Miyako and Ishigaki Islands, originally reported as Rheocricotopus chalybeatus (Edwards, 1929) are identified as R. okifoveatus Sasa, 1990. A new species, Einfeldia sasai is described on the basis of specimens recorded from Minamidato Island, previously incorrectly determined as E. pagana.

A key process of the nonstationary relationship between ENSO and the Western Pacific teleconnection pattern.

Recent studies have discovered an intriguing nonstationary relationship between El Ninõ-Southern Oscillation (ENSO) and the Western Pacific (WP) teleconnection pattern, one of the most prominent winter atmospheric circulation patterns in the North Pacific, with a regime-dependent interdecadal modulation of significant and insignificant correlations. However, the physical process underlying the observed nonstationary ENSO-WP relationship is a puzzle and remains to be elucidated, which is also essential for clarifying the still-debated nontrivial issue on whether the WP is directly forced by ENSO or by midlatitude storm tracks-driven intrinsic processes. Based on empirical orthogonal function (EOF) analysis of the upper-tropospheric teleconnection patterns and associated Rossby wave sources (RWS), we show that the nonstationarity in question is due to the regime-dependent constructive or destructive interference in meridional overturning circulation between the two leading EOFs of RWS best correlated with ENSO and WP, respectively. The observed insignificant correlation between ENSO and the WP after the 1988 regime shift can be explained by interrupted teleconnection between the tropics and high latitudes due to the collapse of the subtropical bridge pillar in the jet entrance region, consequence of the destructive interference. This suggested interference mechanism related to the regime-dependent upper-level RWS fields has significant implications for resolving the puzzle that hinders better understanding of decadal regime behaviors of the climate system in the North Pacific.

The taxonomic implication of frontal tubercles in Polypedilum subgenera diagnoses, with re-description of Polypedilum isigabeceum Sasa & Suzuki (Diptera, Chironomidae).

Polypedilum isigabeceum Sasa et Suzuki, 2000 was described as belonging to subgenus Polypedilum s. str. However, if we accept the conclusion of Sæther et al. (2010), the species might be placed into Kribionympha with P. unagiquartum Sasa, 1985 because of the presence of distinct frontal tubercles in the adult males. However, other taxonomic characters do not support their treatment. P. isigabeceum is re-described and reconfirmed to be assigned to the subgenus Polypedilum s. str. The taxonomic meaning of frontal tubercles is discussed for defining the subgeneric rankings within genus Polypedilum.

A revised subgeneric position for Polypedilum (Probolum) simantokeleum, with description of a new Uresipedilum species in Japan (Diptera: Chironomidae).

Two Japanese Polypedilum species including a new species are redescribed and described based on the males. Polypedilum (Probolum) simantokeleum, Sasa, Suzuki et Sakai, 1998, is transferred to the subgenus Uresipedilum. Polypedilum (Uresipedilum) dissimilum sp. nov. is easily distinguished from other members of Uresipedilum by having a T-shaped tergal band. Definition of the subgenus Probolum is briefly discussed: we suggest Probolum should be defined as the species with the superior volsella bearing inner lobe pending adequate larval information.

[Evaluation of the sensitivity of a densitometry system, in judging the result of influenza virus antigen-detection kit using immunochromatography].

Immunochromatography viral antigen-detection kits have become popular in clinical settings in Japan. Influenza virus detection kit is one of them. It is sometimes used in early phase of the disease, combined with the early treatment with anti-influenza drugs. Most of them are invented to visually read the test line on their kits. However, we should be careful about their reliability of them. Sometimes human errors occur at the visual tests, and they have different sensitivities among the kits from different companies. In this report, we evaluated the sensitivity of BD Veritor System Flu with its reader by comparing with conventional visual tests. A total of 84 people including laboratory technologists were asked to visually read test line and their answers were compared with results of BD Veritor System Reader. This study showed that the lower the concentration of standard sample was applied, the greater the error ratio of visual test became, indicating the stable sensitivity of Veritor System. Moreover, the sensitivity was compared with three other major products approved in Japan, using four influenza viruses: type A of H1N1 seasonal 2009, H1N1 pandemic 2009, H3N2 seasonal 2012 and type B of seasonal 2012. It was indicated that Veritor System had the highest limit of detection from the kits.

CCL2 accelerates microglia-mediated Abeta oligomer formation and progression of neurocognitive dysfunction.

BACKGROUND: The linkages between neuroinflammation and Alzheimer's disease (AD) pathogenesis are well established. What is not, however, is how specific immune pathways and proteins affect the disease. To this end, we previously demonstrated that transgenic over-expression of CCL2 enhanced microgliosis and induced diffuse amyloid plaque deposition in Tg2576 mice. This rodent model of AD expresses a Swedish beta-amyloid (Abeta) precursor protein mutant. METHODOLOGY/PRINCIPAL FINDINGS: We now report that CCL2 transgene expression accelerates deficits in spatial and working memory and hippocampal synaptic transmission in beta-amyloid precursor protein (APP) mice as early as 2-3 months of age. This is followed by increased numbers of microglia that are seen surrounding Abeta oligomers. CCL2 does not suppress Abeta degradation. Rather, CCL2 and tumor necrosis factor-alpha directly facilitated Abeta uptake, intracellular Abeta oligomerization, and protein secretion. CONCLUSIONS/SIGNIFICANCE: We posit that CCL2 facilitates Abeta oligomer formation in microglia and propose that such events accelerate memory dysfunction by affecting Abeta seeding in the brain.

AAV1/2-mediated CNS gene delivery of dominant-negative CCL2 mutant suppresses gliosis, beta-amyloidosis, and learning impairment of APP/PS1 mice.

Accumulation of aggregated amyloid-beta (Abeta) peptide was studied as an initial step for Alzheimer's disease (AD) pathogenesis. Following amyloid plaque formation, reactive microglia and astrocytes accumulate around plaques and cause neuroinflammation. Here brain chemokines play a major role for the glial accumulation. We have previously shown that transgenic overexpression of chemokine CCL2 in the brain results in increased microglial accumulation and diffuse amyloid plaque deposition in a transgenic mouse model of AD expressing Swedish amyloid precursor protein (APP) mutant. Here, we report that adeno-associated virus (AAV) serotype 1 and 2 hybrid efficiently deliver 7ND gene, a dominant-negative CCL2 mutant, in a dose-response manner and express >1,000-fold higher recombinant CCL2 than basal levels after a single administration. AAV1/2 hybrid virus principally infected neurons without neuroinflammation with sustained expression for 6-months. 7ND expressed in APP/presenilin-1 (APP/PS1) bigenic mice reduced astro/microgliosis, beta-amyloidosis, including suppression of both fibrillar and oligomer Abeta accumulation, and improved spatial learning. Our data support the idea that the AAV1/2 system is a useful tool for CNS gene delivery, and suppression of CCL2 may be a therapeutic target for the amelioration of AD-related neuroinflammation.

Cytokine-mediated inhibition of fibrillar amyloid-beta peptide degradation by human mononuclear phagocytes.

Vaccination therapy of AD animal models and patients strongly suggests an active role of brain mononuclear phagocytes in immune-mediated clearance of amyloid-beta peptides (Abeta) in brain. Although Abeta uptake by macrophages can be regulated by pro- and anti-inflammatory cytokines, their effects on macrophage-mediated Abeta degradation are poorly understood. To better understand this mechanism of degradation, we examined whether pro- and anti-inflammatory cytokines affect the degradation of Abeta using primary cultured human monocyte-derived macrophages (MDM) and microglia using pulse-chase analysis of fibrillar and oligomer (125)I-Abeta40 and Abeta42. Initial uptake of fibrillar Abeta40 and Abeta42 was 40% and its degradation was saturated by 120 h in both MDM and microglia, compared with an initial uptake of oligomeric Abeta less than 0.5% and saturation of degradation within 24 h. IFN-gamma increased the intracellular retention of fibrillar Abeta40 and Abeta42 by inhibiting degradation, whereas IL-4, IL-10, and TGF-beta1, but not IL-13 and IL-27, enhanced degradation. Fibrillar Abeta degradation in MDM is sensitive to lysosomal and insulin degrading enzyme inhibitors but insensitive to proteasomal and neprilysin inhibitors. IFN-gamma and TNF-alpha directly reduced the expression of insulin degrading enzyme and chaperone molecules (heat shock protein 70 and heat shock cognate protein 70), which are involved in refolding of aggregated proteins. Coculture of MDM with activated, but not naive T cells, suppressed Abeta degradation in MDM, which was partially blocked by a combination of neutralizing Abs against proinflammatory cytokines. These data suggest that proinflammatory cytokines suppress Abeta degradation in MDM, whereas select anti-inflammatory and regulatory cytokines antagonize these effects.

Phosphorylation of claudin-5 and occludin by rho kinase in brain endothelial cells.

Critical to the proper maintenance of blood-brain-barrier (BBB) integrity are the endothelial tight junctions (TJs). Posttranslational modifications of essential endothelial TJ proteins, occludin and claudin-5, contribute and possibly disrupt BBB integrity. Our previous work has shown that Rho kinase (RhoK) activation mediates occludin and claudin-5 phosphorylation resulting in diminished barrier tightness and enhanced monocyte migration across BBB in the setting of human immunodeficiency virus-1 encephalitis (HIVE). To determine whether RhoK can directly phosphorylate TJ proteins, we examined phosphorylation of cytoplasmic domains of recombinant claudin-5 and occludin by RhoK. We found that RhoK predominately phosphorylated two sites on occludin (T382 and S507) and one site on claudin-5 (T207). Specific anti-phosphopeptide antibodies were developed for these sites, allowing the detection of phosphorylated occludin at T382 and S507, and claudin-5 at T207 from full-length recombinant occludin and claudin-5 transiently expressed in COS-7 cells and mouse brain microvascular endothelial cells. Finally, these phosphospecific antibodies demonstrated enhanced staining of brain endothelial cells in the mouse model for HIVE and human HIVE brains featuring mononuclear cell infiltration across disrupted BBB. Our results demonstrated the direct phosphorylation of occludin and claudin-5 by RhoK at specific sites, which was increased in encephalitic brain tissue. These antibodies could be useful reagents for monitoring BBB dysfunction in vivo.

Kinetic analysis of aggregated amyloid-beta peptide clearance in adult bone-marrow-derived macrophages from APP and CCL2 transgenic mice.

Accumulating evidence suggests that bone-marrow (BM)-derived mononuclear phagocytes have an important role in the clearance of soluble and aggregated amyloid-beta peptides (Abeta) in Alzheimer's disease (AD) brains. However, the exact kinetics of Abeta clearance in mononuclear phagocytes derived from transgenic animal models of AD expressing beta-amyloid precursor protein (APP) mutants have been poorly characterized. We have examined whether CCL2 and APP expression affects the clearance of Abeta in conjunction with our control, acetylated low-density lipoprotein (AcLDL), using primary cultured BM-derived macrophages derived from adult APP, CCL2, APP/CCL2, and control littermates. Pulse-chase analysis demonstrated three distinct destinations for Abeta40 and AcLDL: intracellular retention, degradation, and secretion. As predicted, 50% of Abeta remained intracellularly contained even 5 days after pulse, while 40% of degraded and 14% of nondegraded Abeta were secreted. APP/CCL2 macrophages show reduced intracellular Abeta retention, along with enhanced secretion of both degraded and nondegraded Abeta. Abeta accumulation in aggresome is also partially reduced in APP/CCL2 macrophages as compared to other APP, CCL2, or control groups, suggesting impaired sorting of aggregated Abeta in aggresomes. The degradation of intracranially injected (125)I-Abeta40 aggregates was also enhanced in adult APP/CCL2 mice as compared to APP littermates in vivo. These data suggest that APP and CCL2 synergistically enhance BM-derived macrophage-mediated clearance of Abeta. In contrast, the clearance of AcLDL by BM-derived macrophages was not significantly enhanced by the presence of either APP or CCL2.

Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice.

Reactive astrocytes and microglia in Alzheimer's disease surround amyloid plaques and secrete proinflammatory cytokines that affect neuronal function. Relationship between cytokine signaling and amyloid-beta peptide (Abeta) accumulation is poorly understood. Thus, we generated a novel Swedish beta-amyloid precursor protein mutant (APP) transgenic mouse in which the interferon (IFN)-gamma receptor type I was knocked out (APP/GRKO). IFN-gamma signaling loss in the APP/GRKO mice reduced gliosis and amyloid plaques at 14 months of age. Aggregated Abeta induced IFN-gamma production from co-culture of astrocytes and microglia, and IFN-gamma elicited tumor necrosis factor (TNF)-alpha secretion in wild type (WT) but not GRKO microglia co-cultured with astrocytes. Both IFN-gamma and TNF-alpha enhanced Abeta production from APP-expressing astrocytes and cortical neurons. TNF-alpha directly stimulated beta-site APP-cleaving enzyme (BACE1) expression and enhanced beta-processing of APP in astrocytes. The numbers of reactive astrocytes expressing BACE1 were increased in APP compared with APP/GRKO mice in both cortex and hippocampus. IFN-gamma and TNF-alpha activation of WT microglia suppressed Abeta degradation, whereas GRKO microglia had no changes. These results support the idea that glial IFN-gamma and TNF-alpha enhance Abeta deposition through BACE1 expression and suppression of Abeta clearance. Taken together, these observations suggest that proinflammatory cytokines are directly linked to Alzheimer's disease pathogenesis.

Overexpression of monocyte chemotactic protein-1/CCL2 in beta-amyloid precursor protein transgenic mice show accelerated diffuse beta-amyloid deposition.

Microglia accumulation at the site of amyloid plaques is a strong indication that microglia play a major role in Alzheimer's disease pathogenesis. However, how microglia affect amyloid-beta peptide (Abeta) deposition remains poorly understood. To address this question, we developed a novel bigenic mouse that overexpresses both amyloid precursor protein (APP) and monocyte chemotactic protein-1 (MCP-1; CCL2 in systematic nomenclature). CCL2 expression, driven by the glial fibrillary acidic protein promoter, induced mononuclear phagocyte (MP; monocyte-derived macrophage and microglial) accumulation in the brain. When APP/CCL2 transgenic mice were compared to APP mice, a fivefold increase in Abeta deposition was present despite increased MP accumulation around hippocampal and cortical amyloid plaques. Levels of full-length APP, its C-terminal fragment, and Abeta-degrading enzymes (insulin-degrading enzyme and neprilysin) in APP/CCL2 and APP mice were indistinguishable. Sodium dodecyl sulfate-insoluble Abeta (an indicator of fibrillar Abeta) was increased in APP/CCL2 mice at 5 months of age. Apolipoprotein E, which enhances Abeta deposition, was also increased (2.2-fold) in aged APP/CCL2 as compared to APP mice. We propose that although CCL2 stimulates MP accumulation, it increases Abeta deposition by reducing Abeta clearance through increased apolipoprotein E expression. Understanding the mechanisms underlying these events could be used to modulate microglial function in Alzheimer's disease and positively affect disease outcomes.

Liver metastasis 30 years after enucleation of the left eyeball for choroidal melanoma.

Here, we report a case of 70-year-old female with metastatic choroidal melanoma in the liver, which was detected 30 years after enucleation of the left eyeball. At first, two hypovascular tumors (4cm and 1cm in diameter) were detected in the liver as high-density areas on plain computed tomography (CT). They were demonstrated as hyper- and hypo-intensity lesions on T1- and T2-weighted image of magnetic resonance imaging (MRI), respectively, with superparamagnetic iron oxide uptake. During about 2-years follow-up, the larger tumor did not change significantly in size and in the character. However, the smaller one grew up in size and changed its nature to hypervascular and hyper-intensity on T2-weighted image of MRI. These hypervascular tumors increased in number and in size rapidly. The specimens obtained with tumor biopsy revealed epithelioid tumor cells positive for HMB45 immunohistochemical stain with and without brown pigment, and the tumors were diagnosed as melanoma. The patient underwent transcatheter arterial chemoembolization with cisplatin and epirubicin hydrochloride, and subsequent transcatheter arterial infusion chemotherapy with cisplatin, nimustine and dacarbazine. Unfortunately, however, the tumor rapidly progressed and she died. We discuss the imaging of the melanoma metastasized to the liver with the estimation of doubling time (DT) of the tumors.

Chironomid fauna (Diptera, Chironomidae) in a filtration plant in Japan.

Massive flights of chironomid midges have been observed frequently, and they have caused some problems in the daily life of residents around water treatment works. The development of physical and biological control strategies against chironomid midges is urgently needed because chemical control is not feasible in slow sand filter beds. In this study, in order to collect basic biological data for controlling the massive flights of chironomid midges, seasonal changes in the abundance and species composition of chironomid midges and larvae were investigated in slow sand filter beds. We identified 21 genera and 49 species belonging to 3 subfamilies. In spring, Cricotopus sylvestris and Rheopelopia maculipennis were the dominant species, whereas Polypedilum nubifer, Cricotopus trifasciatus, Chironomus kiiensis, and Procladius sagitalis were dominant in summer. Tanytarsus mendax and T. volgensis were the dominant species in fall. Polypedilum nubifer, C. sylvestris, and C. kiiensis were the major pest species in Japan. The overall factors influencing the abundance pattern of chironomids supposedly are temperature and the quality and quantity of food in slow sand filter beds.

Dose-dependent effect of MK-801 on the levels of neuropeptides processing enzymes in rat brain regions.

The appropriate levels of neuropeptides and their processing enzyme activities are required to continue a normal cell life, and the dysfunction of these peptides and enzymes are responsible for many neuronal abnormalities. Systemic administration of (+) MK-801 (dizocilpine maleate), a noncompetitive N-methyl-[D]-aspartate (NMDA) receptor antagonist, causes both neuroprotective and neurotoxic activities depending on doses and conditions. In the present study, we investigated the dose dependent effect of (+) MK-801 on prolyl endopeptidase (PEP), endopeptidase EC 24.15 (EP 24.15) and beta-D-glucuronidase activities as well as the protein levels of EP 24.15 and neuron specific enolase (NSE) in the posterior cingulate/retrosplenial cortices (PC/RSC), hippocampus, frontal cortex and striatum of female rats 3 days after the treatment. The activity of PEP was significantly increased compared with controls (saline) in the PC/RSC at 1.0 and 5.0 mg/kg doses, and in the frontal cortex at 5.0 mg/kg dose. beta-D-Glucuronidase activity was dose-dependently increased in all brain regions examined. The activity of EP 24.15 was unchanged in all regions after the treatment, whereas the Western blot analysis for EP 24.15 showed the increased protein level in the PC/RSC. These results suggest that a low dose treatment with MK-801 causes neurotoxicity in the PC/RSC and hippocampus, and the high dose treatment causes neurotoxicity in all the brain regions examined.