Advances in Liquid Biopsy for Diagnosis of Bladder Cancer.

Bladder cancer (BCa) is the most common malignancy of the urinary system. It has a high recurrence rate and requires longterm follow-up. Significant advances in BCa research have been made in recent years; however, the initial diagnosis and follow-up of BCa relies on cystoscopy, which is an invasive and expensive procedure. Over the past decade, liquid biopsies (e.g., blood and urine) have proven to be highly efficient methods for the discovery of BCa biomarkers. This noninvasive sampling method is used to analyze unique tumor components released into body fluids and enables serial sampling and longitudinal monitoring of tumor progression. Several liquid biopsy biomarkers have been studied extensively and have shown promising results in the clinical applications of BCa, including early detection, microscopic residual disease detection, recurrence prediction, and treatment response. Therefore, this review aims to provide an update on various new liquid biopsy markers and the advantages and current limitations of liquid biopsy in the diagnosis of BCa.

The Critical Role of Intracellular Bacterial Communities in Uncomplicated Recurrent Urinary Cystitis: A Comprehensive Review of Detection Methods and Diagnostic Potential.

Urinary tract infections (UTIs) are among the most common bacterial infections worldwide and are particularly prevalent in women. Recurrent UTIs significantly diminish quality of life due to their symptoms and frequent relapses. Patients often experience immediate relapse following slightly strenuous activities or intense psychological stress. In this review, we explore why infections persist despite the advent of various treatments and suggest strategies to manage recurrent cystitis by targeting the mechanisms of adhesion and infection. Vitamin D levels and the expression of neutrophil gelatinase-associated lipocalin are linked to the recurrence of UTIs. During a UTI, bacteria employ adhesins to invade the urinary tract, adhere to urothelial cells, and then penetrate these cells, where they rapidly multiply to establish intracellular bacterial communities. Bacteria can also form quiescent intracellular reservoirs that escape immune responses and antibiotic treatments, leading to recurrence under certain conditions. The surface proteins of bacteria and D-mannose are crucial in the adhesion of bacteria to the urothelium. Understanding these processes provides valuable insights into potential therapeutic approaches that focus on preventing bacterial attachment and cluster formation. By disrupting the ability of bacteria to adhere to and form clusters on cells, we can better manage recurrent UTIs and improve patient outcomes.

Issues pertaining to Mg, Zn and Cu in the 2020 Dietary Reference Intakes for Koreans.

In the current years, it has now become necessary to establish standards for micronutrient intake based on scientific evidence. This review discusses issues related to the development of the 2020 Dietary Reference Intakes for Koreans (KDRI) for magnesium (Mg), zinc (Zn), and copper (Cu), and future research directions. Following issues were encountered when establishing the KDRI for these minerals. First, characteristics of Korean subjects need to be applied to estimate nutrient requirements. When calculating the estimated average requirement (EAR), the KDRI used the results of balance studies for Mg absorption and factorial analysis for Zn, which is defined as the minimum amount to offset endogenous losses for Zn and Mg. For Cu, a combination of indicators, such as depletion/repletion studies, were applied, wherein all reference values were based on data obtained from other countries. Second, there was a limitation in that it was difficult to determine whether reference values of Mg, Zn, and Cu intakes in the 2020 KDRI were achievable. This might be due to the lack of representative previous studies on intakes of these nutrients, and an insufficient database for Mg, Zn, and Cu contents in foods. This lack of database for mineral content in food poses a problem when evaluating the appropriateness of intake. Third, data was insufficient to assess the adequacy of Mg, Zn, and Cu intakes from supplements when calculating reference values, considering the rise in both demand and intake of mineral supplements. Mg is more likely to be consumed as a multi-nutrient supplement in combination with other minerals than as a single supplement. Moreover, Zn-Cu interactions in the body need to be considered when determining the reference intake values of Zn and Cu. It is recommended to discuss these issues present in the 2020 KDRI development for Mg, Zn, and Cu intakes in a systematic way, and to find relevant solutions.

Proteomics for Early Detection of Non-Muscle-Invasive Bladder Cancer: Clinically Useful Urine Protein Biomarkers.

Bladder cancer is the fourth most common cancer in men, and most cases are non-muscle-invasive. A high recurrence rate is a critical problem in non-muscle-invasive bladder cancer. The availability of few urine tests hinders the effective detection of superficial and small bladder tumors. Cystoscopy is the gold standard for diagnosis; however, it is associated with urinary tract infections, hematuria, and pain. Early detection is imperative, as intervention influences recurrence. Therefore, urinary biomarkers need to be developed to detect these bladder cancers. Recently, several protein candidates in the urine have been identified as biomarkers. In the present narrative review, the current status of the development of urinary protein biomarkers, including FDA-approved biomarkers, is summarized. Additionally, contemporary proteomic technologies, such as antibody-based methods, mass-spectrometry-based methods, and machine-learning-based diagnosis, are reported. Furthermore, new strategies for the rapid and correct profiling of potential biomarkers of bladder cancer in urine are introduced, along with their limitations. The advantages of urinary protein biomarkers and the development of several related technologies are highlighted in this review. Moreover, an in-depth understanding of the scientific background and available protocols in research and clinical applications of the surveillance of non-muscle bladder cancer is provided.

Long-term effect of simplified dietary education on the nutritional status of patients after a gastrectomy.

Dietary education is regarded as an important and useful tool for influencing nutritional status. Since long, dietary education has been performed to improve the nutritional status of patients after a gastrectomy. This study aimed to investigate the effect of simplified dietary education on the nutritional status of patients after a gastrectomy. A total of 1,150 patients with gastric cancer underwent surgery between March 2014 and October 2015 at the Samsung Medical Center (SMC). Of these, we used the case-control matching method (1:1 match) by stratifying the factors of age and sex and included 100 patients in each group. The clinicopathologic data of the patients for two years after the gastrectomy were prospectively collected and retrospectively analyzed. The educated group (ED, N = 100) was provided with a simplified, ordinary dietary education at regular outpatient clinic visits that occurred at 1, 3, 6, and 12 months after gastrectomy and at 1-year intervals thereafter. The clinicopathologic characteristics and nutritional parameters of the educated group (ED) (N = 100) and the non-educated group (NED) (n = 100) were compared. There were no significant differences between the two groups in terms of clinical characteristics and serological parameters. Nutritional parameters, which included body weight loss, body mass index (BMI) change, and prognostic nutritional index (PNI), were also not significantly different between the two groups. Simplified dietary education at regular outpatient clinic visits was ineffective in reducing weight loss after a subtotal gastrectomy. Further research or other methods may be needed to reduce weight loss after a gastrectomy.

Correction: Wachs, S., et al. Associations between Witnessing and Perpetrating Online Hate in Eight Countries: The Buffering Effects of Problem-Focused Coping. Int. J. Environ. Res. Public Health 2019, 16, 3992.

The authors wish to add the following corrections to their paper published in the International Journal of Environmental Research and Public Health [...].

Associations between Witnessing and Perpetrating Online Hate in Eight Countries: The Buffering Effects of Problem-Focused Coping.

Online hate is a topic that has received considerable interest lately, as online hate represents a risk to self-determination and peaceful coexistence in societies around the globe. However, not much is known about the explanations for adolescents posting or forwarding hateful online material or how adolescents cope with this newly emerging online risk. Thus, we sought to better understand the relationship between a bystander to and perpetrator of online hate, and the moderating effects of problem-focused coping strategies (e.g., assertive, technical coping) within this relationship. Self-report questionnaires on witnessing and committing online hate and assertive and technical coping were completed by 6829 adolescents between 12 and 18 years of age from eight countries. The results showed that increases in witnessing online hate were positively related to being a perpetrator of online hate. Assertive and technical coping strategies were negatively related with perpetrating online hate. Bystanders of online hate reported fewer instances of perpetrating online hate when they reported higher levels of assertive and technical coping strategies, and more frequent instances of perpetrating online hate when they reported lower levels of assertive and technical coping strategies. In conclusion, our findings suggest that, if effective, prevention and intervention programs that target online hate should consider educating young people about problem-focused coping strategies, self-assertiveness, and media skills. Implications for future research are discussed.

A preclinical screen to evaluate pharmacotherapies for the treatment of agitation in dementia.

Agitation associated with dementia is frequently reported clinically but has received little attention in preclinical models of dementia. The current study used a 7PA2 CM intracerebroventricular injection model of Alzheimer's disease (AD) to assess acute memory impairment, and a bilateral intrahippocampal (IH) injection model of AD (aggregated Aß1-42 injections) and a bilateral IH injection model of dementia with Lewy bodies (aggregated NAC61-95 injections) to assess chronic memory impairment in the rat. An alternating-lever cyclic-ratio schedule of operant responding was used for data collection, where incorrect lever perseverations measured executive function (memory) and running response rates (RRR) measured behavioral output (agitation). The results indicate that bilateral IH injections of Aß1-42 and bilateral IH injections of NAC61-95 decreased memory function and increased RRRs, whereas intracerebroventricular injections of 7PA2 CM decreased memory function but did not increase RRRs. These findings show that using the aggregated peptide IH injection models of dementia to induce chronic neurotoxicity, memory decline was accompanied by elevated behavioral output. This demonstrates that IH peptide injection models of dementia provide a preclinical screen for pharmacological interventions used in the treatment of increased behavioral output (agitation), which also establish detrimental side effects on memory.

The impact of implementation of an enteral feeding protocol on the improvement of enteral nutrition in critically ill adults.

BACKGROUND AND OBJECTIVES: The optimal delivery of enteral nutrition (EN) may improve clinical outcomes in critically ill patients; thus, optimal EN protocols should be developed. The purpose of this study was to evaluate the impact of implementing an EN protocol on the improvement of EN practices and on the clinical outcomes of critically ill patients. METHODS AND STUDY DESIGN: This was a retrospective study with prospectively collected data. Multidisciplinary working group developed an evidence-based EN protocol based on an extensive review of literature and existing guidelines. Subjects included patients consecutively admitted to the ICU who received EN for more than 24 hours. EN practices and clinical outcomes were compared before and after implementation of the protocol. RESULTS: A total of 270 patients were included, 134 patients before implementation and 136 after implementation of the protocol. EN was initiated earlier (35.8 vs 87.1 hours, p=0.001) and more patients received EN within 24 hours (59.6% vs 41.0%, p=0.002) after implementation of the protocol. The interval between starting EN and reaching the caloric goal was not different, but more patients reached the caloric goal after implementation (52.2% vs 38.3%, p=0.037). The post-implementation group was given more prokinetics and less parenteral nutrition. The incidences of diarrhea and gastrointestinal bleeding significantly decreased following implementation of the protocol. There was no difference in clinical outcomes including in-hospital mortality and length of hospital and ICU stay. CONCLUSION: The implementation of the EN protocol significantly improved the practices of EN and decreased complications in critically ill patients. Clinical outcomes were not different before and after implementation.

Differences in Friendship Networks and Experiences of Cyberbullying Among Korean and Australian Adolescents.

Cyberbullying is one of the negative consequences of online social interaction. The digital environment enables adolescents to engage in online social interaction beyond the traditional physical boundaries of families, neighborhoods, and schools. The authors examined connections to friendship networks in both online and offline settings are related to their experiences as victims, perpetrators, and bystanders of cyberbullying. A comparative face-to-face survey of adolescents (12-15-year-olds) was conducted in Korea (n = 520) and Australia (n = 401). The results reveal that online networks are partially related to cyberbullying in both countries, showing the size of social network sites was significantly correlated with experience cyberbullying among adolescents in both countries. However there were cultural differences in the impact of friendship networks on cyberbullying. The size of the online and offline networks has a stronger impact on the cyberbullying experiences in Korea than it does in Australia. In particular, the number of friends in cliques was positively related to both bullying and victimization in Korea.

Lack of support for bexarotene as a treatment for Alzheimer's disease.

Bexarotene has been reported to reduce brain amyloid-ß (Aß) levels and to improve cognitive function in transgenic mouse models of Alzheimer's disease (AD). Four groups failed to fully replicate the primary results but the original authors claimed overall support for the general conclusions. Because of its potential clinical importance, the current work studied the effects of bexarotene using two animal species and highly relevant paradigms. Rats were tested for the ability of bexarotene to prevent changes induced by an Aß challenge in the form intracerebroventricular (i.c.v) administration of 7PA2 conditioned medium (7PA2 CM) which contains high levels of Aß species. Bexarotene had no effect on the long-term potentiation of evoked extracellular field excitatory postsynaptic potentials induced by i.c.v. 7PA2 CM. It also had no effect following subcutaneous administration of 2, 5, 10 and 15 mg/kg on behavioral/cognitive impairment using an alternating-lever cyclic-ratio schedule of operant responding in the rat. The effects of bexarotene were further tested using the APPSwFILon, PSEN1*M146L*L286V transgenic mouse model of AD, starting at the time Aß deposits first begin to develop. Mice were sacrificed after 48 days of exposure to 100 mg bexarotene per day. No significant difference between test and control mice was found using a water-maze test, and no significant difference in the number of Aß deposits in cerebral cortex, using two different antibodies, was apparent. These results question the potential efficacy of bexarotene for AD treatment, even if instigated in the preclinical period prior to the onset of cognitive deficits reported for human AD. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.

MRZ-99030 - A novel modulator of Aß aggregation: II - Reversal of Aß oligomer-induced deficits in long-term potentiation (LTP) and cognitive performance in rats and mice.

ß-amyloid1-42 (Aß1-42) is a major endogenous pathogen underlying the aetiology of Alzheimer's disease (AD). Recent evidence indicates that soluble Aß oligomers, rather than plaques, are the major cause of synaptic dysfunction and neurodegeneration. Small molecules that suppress Aß aggregation, reduce oligomer stability or promote off-pathway non-toxic oligomerization represent a promising alternative strategy for neuroprotection in AD. MRZ-99030 was recently identified as a dipeptide that modulates Aß1-42 aggregation by triggering a non-amyloidogenic aggregation pathway, thereby reducing the amount of intermediate toxic soluble oligomeric Aß species. The present study evaluated the relevance of these promising results with MRZ-99030 under pathophysiological conditions i.e. against the synaptotoxic effects of Aß oligomers on hippocampal long term potentiation (LTP) and two different memory tasks. Aß1-42 interferes with the glutamatergic system and with neuronal Ca(2+) signalling and abolishes the induction of LTP. Here we demonstrate that MRZ-99030 (100-500 nM) at a 10:1 stoichiometric excess to Aß clearly reversed the synaptotoxic effects of Aß1-42 oligomers on CA1-LTP in murine hippocampal slices. Co-application of MRZ-99030 also prevented the two-fold increase in resting Ca(2+) levels in pyramidal neuron dendrites and spines triggered by Aß1-42 oligomers. In anaesthetized rats, pre-administration of MRZ-99030 (50 mg/kg s.c.) protected against deficits in hippocampal LTP following i.c.v. injection of oligomeric Aß1-42. Furthermore, similar treatment significantly ameliorated cognitive deficits in an object recognition task and under an alternating lever cyclic ratio schedule after the i.c.v. application of Aß1-42 and 7PA2 conditioned medium, respectively. Altogether, these results demonstrate the potential therapeutic benefit of MRZ-99030 in AD.

Caspase-9 activation and Apaf-1 cleavage by MMP-3.

We have previously demonstrated that matrix metalloprotease-3 (MMP-3) can act inside the cell to trigger apoptosis in response to various cell stresses in dopaminergic neuronal cells. However, the mechanism by which MMP-3 activity leads to caspase-3 activation in apoptotic signaling was not known. In the present study, we found that MMP-3 acts upstream of caspase-9. Overexpression of wild type MMP-3, but not mutant MMP-3, generated the enzymatically active 35kD caspase-9. The caspase-9 activation was absent in MMP-3 knockout cells, but was present when these cells were transfected with wild type MMP-3 cDNA. It was elevated in cells that were under a MMP-3-inducing ER stress condition, and this was attenuated by pharmacologic inhibition and gene knockdown of MMP-3. Incubation of recombinant catalytic domain of MMP-3 (cMMP-3) with procaspase-9 was not sufficient to cause caspase-9 activation, and an additional cytosolic factor was required. cMMP-3 was found to bind to the cytosolic protein Apaf-1, as determined by changes in surface plasmon resonance, and to cleave Apaf-1. Pharmacological inhibition, knockout, and knockdown of MMP-3 attenuated the cleavage. Taken together, the present study demonstrates that MMP-3 leads to caspase-9 activation and suggests that this occurs indirectly via a cytosolic protein, possibly involving Apaf-1.

Novel 5-aryloxypyrimidine SEN1576 as a candidate for the treatment of Alzheimer's disease.

Prefibrillar assembly of amyloid-ß (Aß) is a major event underlying the development of neuropathology and dementia in Alzheimer's disease (AD). This study determined the neuroprotective properties of an orally bioavailable Aß synaptotoxicity inhibitor, SEN1576. Binding of SEN1576 to monomeric Aß 1-42 was measured using surface plasmon resonance. Thioflavin-T and MTT assays determined the ability of SEN1576 to block Aß 1-42-induced aggregation and reduction in cell viability, respectively. In vivo long-term potentiation (LTP) determined effects on synaptic toxicity induced by intracerebroventricular (i.c.v.) injection of cell-derived Aß oligomers. An operant behavioural schedule measured effects of oral administration following i.c.v. injection of Aß oligomers in normal rats. SEN1576 bound to monomeric Aß 1-42, protected neuronal cells exposed to Aß 1-42, reduced deficits in in vivo LTP and behaviour. SEN1576 exhibits the necessary features of a drug candidate for further development as a disease modifying treatment for the early stages of AD-like dementia.

AßPP-overexpressing transgenic rat model of Alzheimer's disease utilizing the Tg2576 mouse protocol.

The current study examined behavioral and histological effects of amyloid-ß (Aß) protein precursor (AßPP) overexpression in transgenic (Tg) rats created using the same gene, mutation, and promoter as the Tg2576 mouse model of Alzheimer's disease (AD). Male Tg+ rats were bred with female wild-type rats to generate litters of hemizygous Tg+ and Tg- offspring. Tg+ rats and Tg- littermates were tested for memory deficits at 4, 8, and 12 months old using a water-maze procedure. There were no significant behavioral differences between Tg+ rats and Tg- littermates at 4 months old but there were significant differences at 8 and 12 months old, and in probe trials at 8 and 12 months old, the Tg+ rats spent significantly less time and covered less distance in the platform zone. Under acquisition of a fixed-consecutive number schedule at 3 months old, Tg- littermates demonstrated a longer latency to learning the response rule than Tg+ rats; while this might seem paradoxical, it is consistent with the role of overexpression of AßPP in learning. Histological analyses revealed activated astrocytes in brains of Tg+ rats but not Tg- littermates at 6 months old, and thioflavin-S positive staining in the hippocampus and cortex of 17-month old Tg+ rats but not Tg- littermates. Quantification of Aß load in the brain at 22 months indicated high levels of Aß38, Aß40, and Aß42 in the Tg+ rats. These data suggest this model might provide a valuable resource for AD research.

Orally bioavailable small molecule drug protects memory in Alzheimer's disease models.

Oligomers of beta-amyloid (Aß) are implicated in the early memory impairment seen in Alzheimer's disease before to the onset of discernable neurodegeneration. Here, the capacity of a novel orally bioavailable, central nervous system-penetrating small molecule 5-aryloxypyrimidine, SEN1500, to prevent cell-derived (7PA2 [conditioned medium] CM) Aß-induced deficits in synaptic plasticity and learned behavior was assessed. Biochemically, SEN1500 bound to Aß monomer and oligomers, produced a reduction in thioflavin-T fluorescence, and protected a neuronal cell line and primary cortical neurons exposed to synthetic soluble oligomeric Aß(1-42). Electrophysiologically, SEN1500 alleviated the in vitro depression of long-term potentiation induced by both synthetic Aß(1-42) and 7PA2 CM, and alleviated the in vivo depression of long-term potentiation induced by 7PA2 CM, after systemic administration. Behaviorally, oral administration of SEN1500 significantly reduced memory-related deficits in operant responding induced after intracerebroventricular injection of 7PA2 CM. SEN1500 reduced cytotoxicity, acute synaptotoxicity, and behavioral deterioration after in vitro and in vivo exposure to synthetic Aß and 7PA2 CM, and shows promise for development as a clinically viable disease-modifying Alzheimer's disease treatment.

Helix-coiled gold nanowires for molecular sensing.

Helix-coiled gold nanowires were fabricated by a templating route using unique composite templates consisting of anodic aluminum oxide (AAO) nanotubular membrane and confined mesoporous silica therein. A different degree of confinement energy induces a different degree of helix curvature of confined porous silica nanochannels in an AAO, which works as a hard template for the electrochemical deposition of gold, thereby rationally enabling a different degree of helix curvature of gold nano-replicas. From surface-enhanced Raman scattering experiments, we first found that helix-coiled gold nanowires show more distinctly enhanced molecule sensing efficiency than those from simple smooth gold nanowires, and gold nanowires with the narrower lateral width show more enhanced molecule sensing efficiency than those of thicker width helix nanowires.

Matrix metalloproteinase-3 is activated by HtrA2/Omi in dopaminergic cells: relevance to Parkinson's disease.

Dopaminergic neurons in the substantia nigra are particularly vulnerable, and their degeneration leads to Parkinson's disease. We have previously reported that matrix metalloproteinase-3 (MMP-3) activity is involved in dopaminergic neurodegeneration by multiple mechanisms and that this requires activation of MMP-3 from proMMP-3 by an intracellular serine protease. HtrA2/Omi is a mitochondrial serine protease that has been shown in non-dopaminergic cells to translocate into the cytosol where it triggers apoptosis. In the present study we sought to determine whether HtrA2/Omi might cause activation of MMP-3 in dopaminergic neuronal cells using CATH.a cell line. Mitochondrial stress induced by rotenone led to MMP-3 activation and HtrA2/Omi translocation into the cytosol. The MMP-3 activation involved HtrA2/Omi, because both pharmacological inhibition and siRNA-induced knockdown of HtrA2/Omi attenuated the activation induced by rotenone or MPP+. Overexpression of mature HtrA2/Omi, but not mutant HtrA2/Omi, resulted in MMP-3 activity increase and cell death. Addition of recombinant and catalytically active HtrA2/Omi to lysate of untreated cells led to activation of the endogenous MMP-3, and incubation of the HtrA2/Omi with recombinant proMMP-3 caused cleavage of proMMP-3 to a 48kD protein, corresponding to the active form, which was accompanied by an increase in MMP-3 activity. Taken together, the data indicate that HtrA2/Omi, which normally exists in the mitochondria, can cause MMP-3 activation in the cytosol under a cell stress condition, which can ultimately lead to demise of dopaminergic neuronal cells.

A novel compound PTIQ protects the nigral dopaminergic neurones in an animal model of Parkinson's disease induced by MPTP.

BACKGROUND AND PURPOSE: In Parkinson's disease, the dopaminergic neurones in the substantia nigra undergo degeneration. While the exact mechanism for the degeneration is not completely understood, neuronal apoptosis and neuroinflammation are thought to be key contributors. We have recently established that MMP-3 plays crucial roles in dopaminergic cell death and microglial activation. EXPERIMENTAL APPROACH: We tested the effects of 7-hydroxy-6-methoxy-2-propionyl-1,2,3,4-tetrahydroisoquinoline (PTIQ) on expression of MMP-3 and inflammatory molecules and dopaminergic cell death in vitro and in an animal model of Parkinson's disease, and Parkinson's disease-related motor deficits. The pharmacokinetic profile of PTIQ was also evaluated. KEY RESULTS: PTIQ effectively suppressed the production of MMP-3 induced in response to cellular stress in the dopaminergic CATH.a cell line and prevented the resulting cell death. In BV-2 microglial cells activated with lipopolysaccharide, PTIQ down-regulated expression of MMP-3 along with IL-1ß, TNF-α and cyclooxygenase-2 and blocked nuclear translocation of NF-κB. In the mouse model of Parkinson's disease ,induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), PTIQ attenuated the associated motor deficits, prevented neurodegeneration and suppressed microglial activation in the substantia nigra. Pharmacokinetic analysis showed it was relatively stable against liver microsomal enzymes, did not inhibit the cytochrome p450 isozymes or the hERG ion channel, exhibited no cytotoxicity on liver cells or lethality when administered at 1000 mg kg(-1) and entered the brain rather rapidly yielding a 28% brain:plasma ratio after i.p. injection. CONCLUSIONS AND IMPLICATIONS: These results suggest PTIQ has potential as a candidate drug for disease-modifying therapy for Parkinson's disease.

Novel anti-inflammatory compound SEN1176 alleviates behavioral deficits induced following bilateral intrahippocampal injection of aggregated amyloid-ß1₋42.

Behavioral effects of a novel anti-inflammatory SEN1176 were investigated. This pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine suppresses amyloid-ß (Aß)1-42-induced macrophage production of nitric oxide, TNF-α, IL-1ß, and IL-6 in a dose-dependent fashion, an activity profile consistent with SEN1176 being a neuroinflammation inhibitor. Using male Sprague-Dawley rats, SEN1176 was examined relative to detrimental behavioral effects induced following bilateral intrahippocampal (IH) injections of aggregated Aß1-42. The rats were trained to respond under an alternating-lever cyclic-ratio (ALCR) schedule of food reinforcement, enabling measurement of parameters of operant performance that reflect aspects of learning and memory. Under the ALCR schedule, orally administered SEN1176 at 5, 20, or 30 mg/kg was effective in reducing the behavioral deficit caused by bilateral IH aggregated Aß1-42 injections in a dose-related manner over a 90-day treatment period. SEN1176 at 20 and 30 mg/kg significantly reduced lever switching errors and, at doses of 5, 10, and 30 mg/kg, significantly reduced incorrect lever perseverations, indicating a reduction of the behavioral deficit induced as a result of inflammation following IH Aß1-42 injections. When treatment with SEN1176 was instigated 30 days after IH Aß1-42 injections, it resulted in progressive protection, and withdrawal of SEN1176 treatment 60 days after IH Aß1-42 injections revealed partial retention of the protective effect. SEN1176 also significantly reduced numbers of activated astrocytes adjacent to the aggregated Aß1-42 injection sites. These results indicate the potential of SEN1176 for alleviating chronic neuroinflammatory processes related to brain Aß deposition that affect learning and memory in Alzheimer's disease.