Comparison of multiple linear regression and machine learning methods in predicting cognitive function in older Chinese type 2 diabetes patients.

INTRODUCTION: The prevalence of type 2 diabetes (T2D) has increased dramatically in recent decades, and there are increasing indications that dementia is related to T2D. Previous attempts to analyze such relationships principally relied on traditional multiple linear regression (MLR). However, recently developed machine learning methods (Mach-L) outperform MLR in capturing non-linear relationships. The present study applied four different Mach-L methods to analyze the relationships between risk factors and cognitive function in older T2D patients, seeking to compare the accuracy between MLR and Mach-L in predicting cognitive function and to rank the importance of risks factors for impaired cognitive function in T2D. METHODS: We recruited older T2D between 60-95 years old without other major comorbidities. Demographic factors and biochemistry data were used as independent variables and cognitive function assessment (CFA) was conducted using the Montreal Cognitive Assessment as an independent variable. In addition to traditional MLR, we applied random forest (RF), stochastic gradient boosting (SGB), Naïve Byer's classifier (NB) and eXtreme gradient boosting (XGBoost). RESULTS: Totally, the test cohort consisted of 197 T2D (98 men and 99 women). Results showed that all ML methods outperformed MLR, with symmetric mean absolute percentage errors for MLR, RF, SGB, NB and XGBoost respectively of 0.61, 0.599, 0.606, 0.599 and 0.2139. Education level, age, frailty score, fasting plasma glucose and body mass index were identified as key factors in descending order of importance. CONCLUSION: In conclusion, our study demonstrated that RF, SGB, NB and XGBoost are more accurate than MLR for predicting CFA score, and identify education level, age, frailty score, fasting plasma glucose, body fat and body mass index as important risk factors in an older Chinese T2D cohort.

Photoreceptor changes in Leber hereditary optic neuropathy with m.G11778A mutation.

AIM: To evaluate the functional and structural changes of photoreceptors in patients and asymptomatic carriers with Leber hereditary optic neuropathy (LHON) using full-field electroretinography (FERG) and optical coherence tomography (OCT). METHODS: Individuals diagnosed with LHON at the Renmin Hospital of Wuhan University and their family members were included in this cross-sectional observational study. The FERG a-wave amplitude of affected patients and asymptomatic carriers was analyzed. The thickness of the outer nuclear layer (ONL), inner and outer segment (IS/OS) and total photoreceptors in the macular fovea and parafovea were measured. RESULTS: This study included 14 LHON patients (mean age: 20.00±9.37y), 12 asymptomatic carriers (mean age: 39.83±6.48y), and 14 normal subjects (mean age: 24.20±1.52y). The FERG results showed that the dark-adapted 3.0 electroretinography and light-adapted 3.0 electroretinography a-wave amplitudes of patients and carriers were significantly decreased (P<0.001). The ONL and photoreceptors layers were slightly thicker in patients than in normal subjects (P<0.05), whereas they were thinner in carriers (P<0.05). There were no differences in IS/OS thickness among the groups (P>0.05). CONCLUSION: Photoreceptors function is significantly impaired in LHON-affected patients and asymptomatic carriers. Meanwhile, photoreceptors morphology is slightly altered, mainly manifesting as a change in ONL thickness.

Comparing Multiple Linear Regression and Machine Learning in Predicting Diabetic Urine Albumin-Creatinine Ratio in a 4-Year Follow-Up Study.

The urine albumin-creatinine ratio (uACR) is a warning for the deterioration of renal function in type 2 diabetes (T2D). The early detection of ACR has become an important issue. Multiple linear regression (MLR) has traditionally been used to explore the relationships between risk factors and endpoints. Recently, machine learning (ML) methods have been widely applied in medicine. In the present study, four ML methods were used to predict the uACR in a T2D cohort. We hypothesized that (1) ML outperforms traditional MLR and (2) different ranks of the importance of the risk factors will be obtained. A total of 1147 patients with T2D were followed up for four years. MLR, classification and regression tree, random forest, stochastic gradient boosting, and eXtreme gradient boosting methods were used. Our findings show that the prediction errors of the ML methods are smaller than those of MLR, which indicates that ML is more accurate. The first six most important factors were baseline creatinine level, systolic and diastolic blood pressure, glycated hemoglobin, and fasting plasma glucose. In conclusion, ML might be more accurate in predicting uACR in a T2D cohort than the traditional MLR, and the baseline creatinine level is the most important predictor, which is followed by systolic and diastolic blood pressure, glycated hemoglobin, and fasting plasma glucose in Chinese patients with T2D.

Night shift work and the risk of metabolic syndrome: Findings from an 8-year hospital cohort.

OBJECTIVES: Studies concerning the risk of metabolic syndrome associated with night work have shown inconsistent findings, due to imprecise working time data and cross-sectional design. We used register-based daily working time data to examine the risk of incident metabolic syndrome associated with night shift work. METHODS: Working time data collected between 2010 and 2018 of 5775 Taiwanese hospital workers were used to identify night shift workers and to calculate the number of night shifts. Metabolic syndrome was identified by annual occupational health examination results, which were linked to the working time data. Logistic regression models and generalized estimating equations were used to examine the association between night shift work and metabolic syndrome and the 5 components of metabolic syndrome. RESULTS: Night shift work is associated with a higher risk of developing metabolic syndrome (adjusted OR = 1.36, 95% CI = 1.04 to 1.78) and high waist circumference (adjusted OR = 1.27, 95% CI = 1.07 to 1.78) compared to day work. Among night shift workers, increased number of night shifts was associated with high blood pressure (adjusted OR = 1.15, 95% CI = 1.01 to 1.31). CONCLUSIONS: Night shift work is associated with metabolic risk factors. Long-term effects of circadian rhythm disruption on metabolic disturbances needs to be further studied.

Association Between Emotional Disorders and Speech and Language Impairments: A National Population-Based Study.

Anxiety and depression are common emotional problems in children and adolescents. This study used a long-term tracking large database to investigate whether the proportion of children who were diagnosed with speech and language impairments were later diagnosed with anxiety or depression were significantly greater than that of matched group of the same age and gender without speech and language impairments. More than 4300 eligible children with speech and language impairments and matched controls were identified and assessed for anxiety and depression. The risk of anxiety and depressive disorders in children with speech and language impairments were examined with Cox regression analyses and adjusting for covariables (gender, age, and comorbidities). The results showed that speech and language impairments were positively associated with anxiety disorders (adjusted hazard ratio [AHR] 2.87, 95% confidence interval [CI] 2.20-3.76) and depressive disorders (AHR 2.51, 95% CI 1.52-4.13). The number of boys with speech and language impairments was more than twofold that of girls, but boys did not different from girls in the risk of anxiety disorders (AHR 0.95, 95% CI 0.75-1.20) and depressive disorders (AHR 0.72, 95% CI 0.47-1.11). Infantile autism and intellectual disabilities were positively associated with anxiety (AHR 1.54, 95% CI 1.07-2.21; AHR 1.47, 95% CI 1.09-1.98), and the latter was positively associated with depression (AHR 1.83, 95% CI 1.06-3.17). In addition to speech and language impairments interventions, our findings supported the necessity of identification and interventions in anxiety and depressive disorders among children with speech and language impairments from elementary school until youth.

Strong association between metabolically-abnormal obesity and gallstone disease in adults under 50 years.

BACKGROUND: Age, obesity, and metabolic syndrome are known risk factors for gallstones; however, the combined impact of these different risk factors on gallstone formation has not yet been examined. METHODS: This retrospective, cross-sectional study involved 3190 participants, including 207 participants (6.5%) with gallstones and 986 (30.9%) with metabolic syndrome. Participants were divided into four phenotypes according to metabolic syndrome and obesity status: 1378 participants were metabolically healthy and non-obese (MHNO); 826 were metabolically healthy but obese (MHO); 185 were metabolically abnormal but not obese (MANO); and 801 participants were metabolically abnormal and obese (MAO). RESULTS: The MAO and MANO phenotypes had more gallstones than the MHO and MHNO phenotypes, regardless of age (< 50 or ≥ 50 years old). Multivariate analyses showed that phenotype was an independent risk factor for gallstones in participants < 50 years old (odds ratio (OR) = 1.73, 95% confidence interval (CI) = 1.32-2.28). Younger participants also had a higher risk of gallstones in the MAO (OR = 5.41, 95% CI = 2.31-12.66), MANO (OR = 3.18, 95% CI = 0.86-11.75), and MHO (OR = 2.17, 95% CI = 0.90-5.22) phenotypes than the MHNO phenotype. CONCLUSIONS: Our retrospective results demonstrate an increased association of gallstones in younger people (< 50 years old) with metabolic syndrome and obesity.

Risk of schizophrenia among people with obsessive-compulsive disorder: A nationwide population-based cohort study.

High comorbidity of obsessive-compulsive disorder (OCD) has been reported in patients with schizophrenia. The sequence of OCD and schizophrenia onset might clarify the underlying pathophysiological relationships between these two disorders, but available evidence is limited. In this study, we used a population-based cohort to investigate the risk of schizophrenia in people with newly diagnosed OCD. Patients who were first diagnosed with OCD from 2000 to 2013 were selected from the Longitudinal Health Insurance Research Database. The non-OCD group was randomly sampled, and matched with the OCD group by gender, age, urbanization level, and income. Cox regression analyses and competing risk model were used to estimate the risk of schizophrenia, adjusting for potential confounding factors. In total, 2009 patients with OCD and 8036 controls were identified. The crude incidences of schizophrenia in the OCD and non-OCD groups were 876.2 per 100,000 person-years and 28.7 per 100,000 person-years, respectively. After adjustment, a substantially higher risk of schizophrenia was observed in the OCD group (hazard ratio = 30.29, 95% confidence interval = 17.91-51.21). Male gender, age of OCD onset before 20 years, and antipsychotic prescription were associated with schizophrenia. Patients with comorbidity of autistic disorder have higher risk of schizophrenia (hazard ratio = 4.63, 95% confidence interval = 1.58-13.56). In conclusion, OCD diagnosis, male gender, age of OCD onset before 20 years, comorbidity of autistic disorder, and antipsychotic use were associated with higher risk of schizophrenia. It is essential for psychiatrists to note that OCD may be the initial presentation of schizophrenia.

Design, synthesis and biological evaluation of substituted aminopyridazin-3(2H)-ones as G0/G1-phase arresting agents with apoptosis-inducing activities.

A series of aminopyridazin-3(2H)-one derivatives has been designed and synthesized. Their antiproliferative activities were evaluated against three human cancer cell lines (SH-SY5Y human neuroblastoma, K562 human myelogenous leukemia and AGS gastric cancer cell lines) using the MTT assay. The preliminary activity test displayed that compound 8a exhibited comparable activities against all test cells with the positive control fluorouracil. Meanwhile compounds 8b, 8e and 9c-e displayed selective antiproliferative activities for SH-SY5Y cells. Furthermore, compounds 8a-b with low-micromole GI50 value for SH-SY5Y cells induced apoptosis with cell cycle arrest at G0/G1 phase in SH-SY5Y cells in a dose-dependent manner.

Discovery of 9H-purins as potential tubulin polymerization inhibitors: Synthesis, biological evaluation and structure-activity relationships.

Two series of N-(4-methoxyphenyl)-N-methyl-9H-purin-6-amines (9a-d and 10a-h) and 9-substituted benzyl-6-chloro-9H-purines (11a-h) were designed and synthesized. Their antiproliferative activities against human myelogenous leukemia (K562), human neuroblastoma (SH-SY5Y) and gastric cancer (AGS) cell lines were evaluated using the MTT assay. The preliminary results indicated that compounds 9d and 11e-h displayed low-micromole GI50 values against all tested cell lines. In addition, compounds 10b and 10d showed wonderful antiproliferative activities towards SH-SY5Y cells with selectivity of >230-fold over K562 and AGS cells. Among them, compounds 9d, 10b, 10d and 11g with good antitumor activities exhibited high selectivity for tumor cell lines over immortalized mouse hippocampal (HT22) cell line. Moreover, compound 9d with sub-micromole GI50 values toward AGS cells exhibited moderate tubulin polymerization inhibitory activity, and induced apoptosis at G2/M phase arrest with a dose-dependent manner in the human AGS cells.

Novel Phosphodiesterase 4 Inhibitor FCPR03 Alleviates Lipopolysaccharide-Induced Neuroinflammation by Regulation of the cAMP/PKA/CREB Signaling Pathway and NF-κB Inhibition.

Overactivation of microglia contributes to the induction of neuroinflammation, which is highly involved in the pathology of many neurodegenerative diseases. Phosphodiesterase 4 (PDE4) represents a promising therapeutic target for anti-inflammation; however, the dose-limiting side effects, such as nausea and emesis, have impeded their clinic application. FCPR03, a novel selective PDE4 inhibitor synthesized in our laboratory, shows little or no emetic potency; however, the anti-inflammatory activities of FCPR03 in vitro and in vivo and the molecular mechanisms are still not clearly understood. This study was undertaken to delineate the anti-inflammatory effects of FCPR03 both in vitro and in vivo and explore whether these effects are regulated by PDE4-mediated signaling pathway. BV-2 microglial cells stimulated by lipopolysaccharide (LPS) and mice injected i.p. with LPS were established as in vitro and in vivo models of inflammation. Our results showed that FCPR03 dose dependently suppressed the production of tumor necrosis factor α, interleukin-1ß, and iinterleukin-6 in BV-2 microglial cells treated with LPS. The role of FCPR03 in the production of proinflammatory factors was reversed by pretreatment with protein kinase A (PKA) inhibitor H89. In addition, FCPR03 reduced the levels of proinflammatory factors in the hippocampus and cortex of mice injected with LPS. Our results further demonstrated that FCPR03 effectively increased the production of cAMP, promoted cAMP response element binding protein (CREB) phosphorylation, and inhibited nuclear factor κB (NF-κB) activation both in vitro and in vivo. Our findings suggest that FCPR03 inhibits the neuroinflammatory response through the activation of cAMP/PKA/CREB signaling pathway and NF-κB inhibition.

Discovery of N-Alkyl Catecholamides as Selective Phosphodiesterase-4 Inhibitors with Anti-neuroinflammation Potential Exhibiting Antidepressant-like Effects at Non-emetic Doses.

Depression involving neuroinflammation is one of the most common disabling and life-threatening psychiatric disorders. Phosphodiesterase 4 (PDE4) inhibitors produce potent antidepressant-like and cognition-enhancing effects. However, their clinical utility is limited by their major side effect of emesis. To obtain more selective PDE4 inhibitors with antidepressant and anti-neuroinflammation potential and less emesis, we designed and synthesized a series of N-alkyl catecholamides by modifying the 4-methoxybenzyl group of our hit compound, FCPE07, with an alkyl side chain. Among these compounds, 10 compounds displayed submicromolar IC50 values in the mid- to low-nanomolar range. Moreover, 4-difluoromethoxybenzamides 10g and 10j, bearing isopropyl groups, exhibited the highest PDE4 inhibitory activities, with IC50 values in the low-nanomolar range and with higher selectivities for PDE4 (approximately 5000-fold and 2100-fold over other PDEs, respectively). Furthermore, compound 10j displayed anti-neuroinflammation potential, promising antidepressant-like effects, and a zero incidence rate of emesis at 0.8 mg/kg within 180 min.

Development of highly potent phosphodiesterase 4 inhibitors with anti-neuroinflammation potential: Design, synthesis, and structure-activity relationship study of catecholamides bearing aromatic rings.

In this study, catecholamides (7a-l) bearing different aromatic rings (such as pyridine-2-yl, pyridine-3-yl, phenyl, and 2-chlorophenyl groups) were synthesized as potent phosphodiesterase (PDE) 4 inhibitors. The inhibitory activities of these compounds were evaluated against the core catalytic domains of human PDE4 (PDE4CAT), full-length PDE4A4, PDE4B1, PDE4C1, and PDE4D7 enzymes, and other PDE family members. Eight of the synthesized compounds were identified as having submicromolar IC50 values in the mid-to low-nanomolar range. Careful analysis on the structure-activity relationship of compounds 7a-l revealed that the replacement of the 4-methoxy group with the difluoromethoxy group improved inhibitory activities. More interesting, 4-difluoromethoxybenzamides 7i and 7j exhibited preference for PDE4 with higher selectivities of about 3333 and 1111-fold over other PDEs, respectively. In addition, compound 7j with wonderful PDE4D7 inhibitory activities inhibited LPS-induced TNF-α production in microglia.

Mel-18 negatively regulates stem cell-like properties through downregulation of miR-21 in gastric cancer.

Mel-18, a polycomb group protein, has been reported to act as a tumor suppressor and be down-regulated in several human cancers including gastric cancer. It was also found that Mel-18 negatively regulates self-renewal of hematopoietic stem cells and breast cancer stem cells (CSCs). This study aimed to clarify its role in gastric CSCs and explore the mechanisms. We found that low-expression of Mel-18 was correlated with poor prognosis and negatively correlated with overexpression of stem cell markers Oct4, Sox2, and Gli1 in 101 gastric cancer tissues. Mel-18 was down-regulated in cultured spheroid cells, which possess CSCs, and overexpression of Mel-18 inhibits cells sphere-forming ability and tumor growth in vivo. Besides, Mel-18 was lower-expressed in ovary metastatic lesions compared with that in primary lesions of gastric cancer, and Mel-18 overexpression inhibited the migration ability of gastric cancer cells. Interestingly, overexpression of Mel-18 resulted in down-regulation of miR-21 in gastric cancer cells and the expression of Mel-18 was negatively correlated with the expression of miR-21 in gastric cancer tissues. Furthermore, miR-21 overexpression partially restored sphere-forming ability, migration potential and chemo-resistance in Mel-18 overexpressing gastric cancer cells. These results suggests Mel-18 negatively regulates stem cell-like properties through downregulation of miR-21 in gastric cancer cells.

Involvement of norepinephrine and serotonin system in antidepressant-like effects of hederagenin in the rat model of unpredictable chronic mild stress-induced depression.

CONTEXT: Previous studies from our laboratory indicated that both acute and subchronic administration of Fructus Akebiae (FAE) [the fruit of Akebiae quinata (Thunb.) Decne, (Lardizabalaceae)] produce antidepressant-like effects in animal depressive behavior tests. FAE contains approximately 70% of hederagenin (HG) as its main chemical component. OBJECTIVE: This study compared the antidepressant ability of FAE with that of HG in mice and further investigated the antidepressant-like effects and potential mechanisms of HG in rats subjected to unpredictable chronic mild stress (UCMS). MATERIALS AND METHODS: Mice received FAE (50 mg/kg) and HG (20 mg/kg) once a day via intragastric administration (i.g.) for 3 weeks. The anxiolytic and antidepressant activities of FAE and HG were compared using elevated plus maze (EPM) and behavioral despair tests including tail suspension test (TST) and forced swimming test (FST), respectively. Antidepressant effects of HG (5 mg/kg) were assessed using the UCMS depressive rat model. Moreover, the levels of monoamine neurotransmitters and relevant gene expression in UCMS rats' hippocampi were determined through high-performance liquid chromatography with electrochemical detection and real-time polymerase chain reaction techniques. RESULTS: The results of our preliminary screening test suggest that HG at 20 mg/kg, while not FAE at 50 mg/kg, significantly decreased the immobility in both TST and FST compared with the vehicle group when administered chronically; however, there were no significant differences observed between the HG and the FAE group. Chronic administration of HG failed to significantly reverse the altered crossing and rearing behavioral performance, time spent in the open arm and closed entries in the EPM, even if they showed an increased tendency, but HG significantly increased the percent of sucrose preference in the sucrose preference test (SPT) and decreased the immobility time in the FST. HG showed that significant increases of norepinephrine and serotonin levels and exhibited a tendency to increase the expression of 5-hydroxytryptamine (serotonin) 1A receptor mRNA, and to significantly decrease the expression of the mRNA for the serotonin transporter (5-HTT). However, there were no significant differences in the expression of the brain-derived neurotrophic factor. CONCLUSION: These findings confirm the antidepressant-like effects of HG in a behavioral despair test and UCMS rat model, which may be associated with monoamine neurotransmitters and 5-HTT mRNA expression.

Chlorbipram: a novel PDE4 inhibitor with improved safety as a potential antidepressant and cognitive enhancer.

Major depressive disorder is a common, but serious, psychiatric dysfunction that affects 21% of the population worldwide. Rolipram, a first-generation phosphodiesterase-4 (PDE4) inhibitor, has been shown to have significant antidepressant and cognitive enhancement effects; however, it was unsuccessful in clinic trials because of PDE4-dependent side effects such as nausea and emesis. In this study, we investigated the neuropharmacology of the novel PDE4 inhibitor chlorbipram and the classical PDE4 inhibitor rolipram. Using antidepressant-sensitive behavioral tests, we demonstrated that the acute single administration of chlorbipram (0.075-0.6 mg/kg) produced antidepressant-like effects, as evidenced by decreases in the duration of immobility in Kunming mice in the forced swim and tail suspension tests, and no significant changes in locomotor activity. Scopolamine-induced cognitive dysfunction was also significantly attenuated in the Morris water maze test after the treatment of Sprague Dawley rats with different doses of chlorbipram (0.5-1.5mg/kg). Furthermore, we evaluated the emetic potential of chlorbipram in beagle dogs. After oral administration, 0.5mg/kg rolipram showed emetic profiles in all dogs within 20 minutes, whereas chlorbipram did not induce any emesis during the 120-min observation period, even at the 1.0mg/kg dose. Together, our data suggest that chlorbipram is a novel antidepressant and cognitive enhancer with little or no emetic potency.

The phosphodiesterase-4 inhibitor rolipram reverses Aß-induced cognitive impairment and neuroinflammatory and apoptotic responses in rats.

ß-amyloid (Aß) peptides play an important role in cognition deficits, neuroinflammation, and apoptosis observed in Alzheimer's disease (AD). Activation of cyclic AMP (cAMP) signalling enhances memory and inhibits inflammatory and apoptotic responses. However, it is not known whether inhibition of phosphodiesterase-4 (PDE4), a critical controller of intracellular cAMP concentrations, affects AD-associated neuroinflammatory and apoptotic responses and whether these responses contribute to deficits of memory mediated by cAMP signalling. We addressed these issues using memory tests and neurochemical measures. Specifically, rats microinfused with aggregated Aß25-35 (10 µg/side) into bilateral CA1 subregions displayed deficits in learning ability and memory, as evidenced by decreases in escape latency during acquisition trials and exploratory activities in the probe trial in the water-maze task and 24-h retention in the passive avoidance test. These effects were reversed by rolipram (0.1, 0.25 and 0.5 mg/kg.d i.p.), a prototypic PDE4 inhibitor, in a dose-dependent manner. Interestingly, Aß25-35-treated rats also displayed decreases in expression of phosphorylated cAMP response-element binding protein (pCREB) and Bcl-2, but increases in expression of NF-κB p65 and Bax in the hippocampus; these effects were also reversed by rolipram in a dose-dependent manner. Similar neurochemical results were observed by replacing Aß25-35 with Aß1-42, a full-length amyloid peptide that quickly forms toxic oligomers. These results suggest that PDE4 inhibitors such as rolipram may reverse Aß-induced memory deficits at least in part via the attenuation of neuronal inflammation and apoptosis mediated by cAMP/CREB signalling. PDE4 could be a target for treatment of memory loss associated with AD.

Promotion of ß-amyloid production by C-reactive protein and its implications in the early pathogenesis of Alzheimer's disease.

C-reactive protein (CRP) and ß-amyloid protein (Aß) are involved in the development of Alzheimer's disease (AD). However, the relationship between CRP and Aß production is unclear. In vitro and in vivo experiments were performed to investigate the association of CRP with Aß production. Using the rat adrenal pheochromocytoma cell line (PC12 cells) to mimic neurons, cytotoxicity was evaluated by cell viability and supernatant lactate dehydrogenase (LDH) activity. The levels of amyloid precursor protein (APP), beta-site APP cleaving enzyme (BACE-1), and presenilins (PS-1 and PS-2) were investigated using real-time polymerase chain reaction and Western blotting analysis. Aß1-42 was measured by enzyme-linked immunosorbent assay. The relevance of CRP and Aß as well as potential mechanisms were studied using APP/PS1 transgenic (Tg) mice. Treatment with 0.5-4.0 µM CRP for 48 h decreased cell viability and increased LDH leakage in PC12 cells. Incubation with CRP at a sub-toxic concentration of 0.2 µM increased the mRNA levels of APP, BACE-1, PS-1, and PS-2, as well as Aß1-42 production. CRP inhibitor reversed the CRP-induced upregulations of the mRNA levels of APP, BACE-1, PS-1, and PS-2, and the protein levels of APP, BACE-1, PS-1, and Aß1-42, but did not reversed Aß1-42 cytotoxicity. The cerebral levels of CRP and Aß1-42 in APP/PS1 Tg mice were positively correlated, accompanied with the elevated mRNA expressions of serum amyloid P component (SAP), complement component 1q (C1q), and tumor necrosis factor-α (TNF-α). These results suggest that CRP cytotoxicity is associated with Aß formation and Aß-related markers expressions; CRP and Aß were relevant in early-stage AD; CRP may be an important trigger in AD pathogenesis.

Prevention of cerebral ischemia-induced memory deficits by inhibition of phosphodiesterase-4 in rats.

Inhibition of phosphodiesterase-4 (PDE4) by rolipram, a prototypical PDE4 inhibitor, reverses memory impairment produced pharmacologically or genetically. Comparably, much less is known about the effect of rolipram on cerebral ischemia-induced memory deficits. The objective of this study was to determine the effects of rolipram on ischemia-induced memory deficit, neuronal damage, and alteration of PDE4 activity in the hippocampus. Memory was examined using Morris water-maze and step-through passive avoidance tests in rats subjected to global cerebral ischemia with or without repeated treatment with rolipram (0.3 or 1 mg/kg, i.p.); neuronal damage in the hippocampus and PDE4 activity in hippocampal tissues were determined using Nissl staining and HPLC, respectively. In the water-maze test, cerebral ischemia significantly increased the escape latency to reach the platform during acquisition training and decreased the exploration time in the target quadrant in the probe trial test; these were blocked by rolipram in a dose-dependent manner. Rolipram also reduced the distracted platform searches induced by cerebral ischemia. In the passive avoidance test, ischemia decreased the 24-h latency to the dark compartment, which was also blocked by rolipram treatment. In addition, Nissl staining revealed ischemia-induced neuron loss in hippocampal CA1; this was blocked by rolipram. Further, cerebral ischemia led to increases in activity of PDE, primarily PDE4, in the hippocampus, which also was antagonized by rolipram. These results suggest that rolipram prevents cerebral ischemia-induced memory deficits via inhibition of increased PDE4 activity and attenuation of hippocampal, neuronal damages induced by ischemia. PDE4 may be a target for treatment of cognitive disorders associated with cerebral ischemia.