Central Nervous System Effects Research Articles

Chinese Expert Consensus on Management of Special Adverse Effects Associated with Lorlatinib

间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）融合基因是非小细胞肺癌（non-small cell lung cancer, NSCLC）中第二常见的肿瘤驱动基因。作为新型的第三代ALK酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI），洛拉替尼对多种ALK激酶域突变具有广谱且高效的临床活性，并具有强大的穿透血脑屏障效力。洛拉替尼的总体耐受性良好，其独特的不良反应或不良事件包括高脂血症与中枢神经系统反应等，多为轻至中度，通常经剂量调整和/或标准医疗干预即可管理。对于ALK阳性晚期NSCLC，开始洛拉替尼治疗前应充分评估患者基线特征与既往用药状况，预先告知患者可能经历的用药相关不良反应，并定期监测以实现药物临床获益的最大化。同时，多学科专家团队对于建立全面的诊断和治疗策略是至关重要的。

Anti-inflammatory and antinociceptive effect of Hyptis martiusii BENTH leaves essential oil

Hyptis martiusii Benth. also known as "cidreira brava", has some activities verified in the literature, such as antiulcerogenic, antimicrobial and antiedematogenic. This study aimed to verify the anti-inflammatory and antinociceptive effect of the leaves essential oil. For the evaluation of the anti-inflammatory activity of OEHM (100 mg/kg/p.o.), models paw edema induced by dextran and histamine, peritonitis and vascular permeability were used. Regarding the anti-nociceptive activity of the OEHM, abdominal contortion tests by acetic acid, formalin, hot plate (50.75 and 100 mg/kg/p.o.), open field and mechanical plantar hyper-nociception (100 mg/kg/p.o.) were carried out. OEHM (100 mg/kg) showed anti-inflammatory activity, being able to remarkably deducing the paw edema induced by dextran and histamine, the total number of cell leukocytes/neutrophils in peritonitis, and exudate in vascular permeability. In antinociceptive activity, the OEHM did not promote significant effect in central nervous system in the open field assay, remarkably reduced abdominal contortions (50, 75 and 100 mg/kg), the time in the formalin assay and the mechanical hyper-nociception (100 mg/kg); however, only doses between 75 and 100 mg/kg were capable of ameliorating the reponse latency time. Regarding the probable mechanism of action, the antinociceptive activity includes the participation in the activation of opioid, TRPV1, and α2-noradrenergic systems. In short, data obtained here reveal that OEHM has anti-inflammatory and antinociceptive activity, implying that its action may be involved in the mechanism of inhibition or liberation of pro-inflammatory mediators involved in pain and inflammation.

Cognitive Impairment Analysis of Myotonic Dystrophy via Weakly Supervised Classification of Neuropsychological Features.

The myotonic dystrophies (DM1 and DM2) are dominantly inherited disorders that cause pathological changes throughout the body. Many individuals with DM experience cognitive, behavioral and other functional central nervous system effects that impact their quality of life. The extent of psychological impairment that will develop in each patient is variable and unpredictable. Hence, it is difficult to get strong supervision information like fully ground truth labels for all cognitive involvement patterns. This study is to assess cognitive involvement among healthy controls and patients with DM. The DM cognitive impairment pattern observation is modeled in a weakly supervised setting and supervision information is used to transform the input feature space to a more discriminative representation suitable for pattern observation. This study incorporated results from 59 adults with DM and 92 control subjects. The developed system categorized the neuropsychological testing data into five cognitive clusters. The quality of the obtained clustering solution was assessed using an internal validity metric. The experimental results show that the proposed algorithm can discover interesting patterns and useful information from neuropsychological data, which will be be crucial in planning clinical trials and monitoring clinical performance. The proposed system resulted in an average classification accuracy of 88%, which is very promising considering the unique challenges present in this population.

Comparative study of the efficacy between 0.5% bupivacaine and 0.5% bupivacaine-dexamethasone 8mg combination in supraclavicular brachial plexus block

Background: Initially the concept of pain was emotional rather than a sensory modality. The word pain is acquired from the Greek word poine which means “penalty”.1 The International Association for the Study of Pain (IASP) described pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage”.2 Peripheral nerve blocks have become a popular anaesthetic option in the perioperative management of patients because nerve blocks provide better postoperative analgesia than does general anaesthesia, while avoiding the cardiopulmonary and central nervous system effects of general anaesthesia. Peripheral nerve block is a technique which uses local anaesthetic to be deposited around a target nerve and block the conduction of action potential thus not allowing pain signals to be transmitted to the pain centre in the brain. Materials & methods: A prospective randomised single blinded study was conducted at Vinayaka Missions Kirupananda Variyar Medical College & Hospitals, Salem from December 2019 to May 2021.

Elevated Plasma Soluble ST2 Levels are Associated With Neuronal Injury and Neurocognitive Impairment in Children With Cerebral Malaria.

Background:Murine experimental cerebral malaria studies suggest both protective and deleterious central nervous system effects from alterations in the interleukin-33 (IL-33)/ST2 pathway.Methods:We assessed whether soluble ST2 (sST2) was associated with neuronal injury or cognitive impairment in a cohort of Ugandan children with cerebral malaria (CM, n=224) or severe malarial anemia (SMA, n=193).Results:Plasma concentrations of sST2 were higher in children with CM than in children with SMA or in asymptomatic community children. Cerebrospinal fluid (CSF) sST2 levels were elevated in children with CM compared with North American children. Elevated plasma and CSF ST2 levels in children with CM correlated with increased endothelial activation and increased plasma and CSF levels of tau, a marker of neuronal injury. In children with CM who were ≥5 years of age at the time of their malaria episode, but not in children <5 years of age, elevated risk factor-adjusted plasma levels of sST2 were associated with worse scores for overall cognitive ability and attention over a 2-year follow-up.Conclusions:The study findings suggest that sST2 may contribute to neuronal injury and long-term neurocognitive impairment in older children with CM.

Abstract 5461: H002: A wide spectrum, highly selective fourth-generation EGFR inhibitor overcoming resistance harboring C797S mutation in NSCLC

Abstract BACKGROUND: Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a major challenge in non-small cell lung cancer (NSCLC) treatment. EGFR activating mutations, such as exon 19 deletions (Del19) and L858R substitution, have been reported in 10-50% of patients with NSCLC. Although these patients respond well to early generations of TKIs, acquired resistance by mechanisms such as T790M mutation compromises their efficacy. Recently, the C797S mutation in combination with Del19 or L858R, and with T790M, has emerged as one of the most common mechanisms underlying on-target resistance to a third generation EGFR TKI, osimertinib. We are developing a fourth-generation EGFR inhibitor, H002, with a wide spectrum and high selectivity to address the growing unmet needs in NSCLC patients harboring C797S mutation. METHODS: H002’s selectivity was assessed by KINOMEscan against more than 400 human kinases. A panel of 44 kinases was further evaluated to enable early identification of off-target effect. In vitro and in vivo anti-tumor efficacy was determined in drug-resistant mutant cell lines, CDX and PDX models. Single mutants (Del or L858R), double mutants (Del/T790M or L858R/T790M) and triple mutants (Del/T790M/C797S or L858R/T790M/C797S) as well as wild type EGFR were assessed. Drug metabolism and pharmacokinetic (DMPK) properties were further assessed. H002’s safety profile was evaluated in rats and beagle dogs, and by hERG potassium channel assay. Acute toxicity, and repeated dose GLP toxicity studies were also conducted in IND-enabling studies. RESULTS: High kinase selectivity and very low off-target effects were demonstrated by kinome-wide profiling and safety screening. H002 was highly active against all forementioned single, double or triple EGFR mutants (IC50 &amp;lt; 5 nM), and highly selective against wild type EGFR. H002 also exhibited potent anti-tumor effects in a dose-dependent manner in various CDX and PDX models. Excellent PK properties were observed in rats and beagle dogs with bioavailability over 70%. H002 was shown to cross the blood-brain barrier post i.g. administration in rats. No adverse effects of respiratory, cardiovascular and central nervous system were observed in safety studies. Repeated-dose toxicity studies only showed EGFR-related adverse reactions, such as gastrointestinal and liver toxicity, with high safety margin over 10-folds. CONCLUSION: H002 has been demonstrated as a promising next generation EGFR inhibitor, with high selectivity, a wide spectrum and potent anti-tumor activity against various EGFR activating mutations, favorable DMPK and safety profiles. It will be further developed as a fourth-generation EGFR inhibitor to overcome drug resistance in NSCLC. Citation Format: Wei Huang, Lin Zhu, Xiaoe Yan, Xin Huang, Jia Hao, Shan Li, Xiangyu Li, Zhiming Chen, Yunchuan Jia, Haibo Li, Jianming Zhang, Xianming Deng, Caihong Yun. H002: A wide spectrum, highly selective fourth-generation EGFR inhibitor overcoming resistance harboring C797S mutation in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5461.

Studies on some neuropharmacological properties of Nevirapine in mice.

Nevirapine (NVP) is non-nucleoside reverse transcriptase inhibitor and an anti-retroviral drug (ARV) with the highest BBB penetrating ability. Its specific pharmacologic effects on central nervous system (CNS) are not well known. The objective of the study was to investigate some CNS effects of Nevirapine. Oral acute toxicity test (Lorke, 1983) was used to estimate the LD50. Exploratory or sedative effects were tested using open field test(OFT), Hole-board test (HBT), diazepam-induced sleeping time test, and ketamine-induced sleeping time test. Five groups of mice were used (5 mice /group). The negative control group received vehicle (distilled water) (10mL /kg) while groups II, III, and IV received NVP- 15.625mg/kg, 31.25mg/kg, 62.5mg/kg body weight respectively while group V received 0.25mg/kg of diazepam intraperitoneal. Groups I to IV were treated orally. The oral LD50 was determined to be 2154. 07mg/kg. NVP, in a dose dependent fashion, increased the number of line-crossing in the OFT. Also, NVP in a dose-dependent fashion, significantly reduced the duration of diazepam-induced sleeping time as well as delayed onset. NVP significantly potentiated ketamine-induced sleeping time duration. Nevirapine possess excitatory effects possibly through antagonism of GABA receptors. Nevirapine causes wakefulness (shortening of sleep) possibly via antagonism of GABAergic neurotransmission.

Approach and management of histamine imbalance in functional medicine

Histamine is known as a substance that causes allergies and anaphylaxis, but, in fact, it is a kind of inflammatory cytokine which is involved in immune and inflammatory responses that protect from external materials. Especially, it is involved in the removal of dust, parasites, and bacteria. Histamine mainly plays a role in physically washing or sterilizing these substances through vasodilation, increasing mucus secretion and expectoration, smooth muscle contraction, and gastric acid secretion. In addition, histamine has central nervous system effects such as arousal and memory, because it is necessary to remember and avoid harmful exposures. Like other cytokines, histamine must be produced, released, and degraded in a balance for proper action. When this balance is broken, various non-specific symptoms from histamine excess, such as rhinitis, urticarial, itching sense, abdominal cramp, diarrhea, epigastric burning, chronic cough, headache, dizziness, edema, insomnia, nervousness and irritability can be appeared. It is defined as “histamine imbalance” in functional medicine, and some researchers are called it as “histamine syndrome”. There can be several causes, but allergies and chronic subclinical inflammation are particularly important. The importance of histamine imbalance is increasing because there are many factors for subclinical inflammation in modern society, such as environmental pollution including fine dust, lack of sleep and exercise, increased carbohydrate consumption with decreased vitamin and mineral intake, and infectious disease like Coronavirus disease-2019. In this review, the authors will propose the concept of histamine imbalance and its functional medical approach and management.

Polydatin as a therapeutic alternative for central nervous system disorders: A systematic review of animal studies.

Polydatin, or piceid, is a natural stilbene found in grapes, peanuts, and wines. Polydatin presents pharmacological activities, including neuroprotective properties, exerting preventive and/or therapeutic effects in central nervous system (CNS) disorders. In the present study, we summarize and discuss the neuroprotective effects of polydatin in CNS disorders and related pathological conditions in preclinical animal studies. A systematic review was performed by searching online databases, returning a total of 110 records, where 27 articles were selected and discussed here. The included studies showed neuroprotective effects of polydatin in experimental models of neurological disorders, including cerebrovascular disorders, Parkinson's disease, traumatic brain injuries, diabetic neuropathy, glioblastoma, and neurotoxicity induced by chemical agents. Most studies were focused on stroke (22.2%) and conducted in male rodents. The intervention protocol with polydatin was mainly acute (66.7%), with postdamage induction treatment being the most commonly used regimen (55.2%). Overall, polydatin ameliorated behavioral dysfunctions and/or promoted neurological function by virtue of its antioxidant and antiinflammatory properties. In summary, this review offers important scientific evidence for the neuroprotective effects and distinct pharmacological mechanisms of polydatin that not only enhances the present understanding but is also useful for the development of future preclinical and clinical investigations.

A review of the chemical constituents and pharmacological activities of Antirrhinum majus (snapdragon)

(common snapdragon) is a flowering plant species in the Antirrhinum genus. It was traditionally used as a diuretic and to treat scurvy, liver problems, and tumours. The leaves and flowers were used to treat tumours and ulcers as antiphlogistic, resolvent, stimulant, and poultices. Amino acids, pigments, oils, anthocyanidins, flavonols, flavones, aurones, flavanones, cinnamic acids, and a variety of other compounds were found in has antimicrobial, insecticidal, cytotoxic, antioxidant, central and peripheral nervous system effects, and many other biological activities, according to recent studies. The chemical constituents and biological effects of are highlighted in this review.

Alterations in white matter microstructural properties after lingual strength exercise in patients with dysphagia.

Central nervous system effects of lingual strengthening exercise to treat dysphagia remain largely unknown. This pilot study measured changes in microstructural white matter to capture alterations in neural signal processing following lingual strengthening exercise. Diffusion-weighted images were acquired from seven participants with dysphagia of varying etiologies, before and after lingual strengthening exercise (20 reps, 3×/day, 3 days/week, 8 weeks), using a 10-min diffusion sequence (9 b0, 56 directions with b1000) on GE750 3T scanner. Tract-Based Spatial Statistics evaluated voxel-based group differences for fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity and local diffusion homogeneity (LDH). Paired t-tests evaluated treatment differences on each metric (P < 0.05). After lingual strengthening exercise, lingual pressure generation increased (avg increase = 46.1 hPa; nonsignificant P = 0.52) with these changes in imaging metrics: (1) decrease in fractional anisotropy, forceps minor; (2) increase in mean diffusivity, right inferior fronto-occipital fasciculus (IFOF); (3) decrease in mean diffusivity, left uncinate fasciculus; (4) decrease in axial diffusivity, both left IFOF and left uncinate fasciculus; (5) increase in LDH, right anterior thalamic radiation and (6) decrease in LDH, temporal portion of right superior longitudinal fasciculus. There was a positive correlation between diffusion tensor imaging metrics and change in lingual pressure generation in left IFOF and the temporal portion of right superior longitudinal fasciculus. These findings suggest that lingual strengthening exercise can induce changes in white matter structural and functional properties in a small group of patients with dysphagia of heterogeneous etiologies. These procedures should be repeated with a larger group of patients to improve interpretation of overall lingual strengthening exercise effects on cortical structure and function.

Gap detection responses modelled using the Hill equation in adults with well-controlled HIV

Objective This study’s objective was determining whether gap detection deficits are present in a longstanding cohort of people living with HIV (PLWH) compared to those living without HIV (PLWOH) using a new gap detection modelling technique (i.e. fitting gap responses using the Hill equation and analysing the individual gap detection resulting curves with non-linear statistics). This approach provides a measure of both gap threshold and the steepness of the gap length/correct detection relationship. Design The relationship between the correct identification rate at each gap length was modelled using the Hill equation. Results were analysed using a nonlinear mixed-effect regression model. Study sample 45 PLWH (age range 41–78) and 39 PLWOH (age range 38–79) were enrolled and completed gap detection testing. Results The likelihood ratio statistic comparing the full regression model with the HIV effects to the null model, assuming one population curve for both groups, was highly significant (p < 0.001), suggesting a less precise relationship between gap length and correct detection in PLWH. Conclusions PLWH showed degraded gap detection ability compared to PLWOH, likely due to central nervous system effects of HIV infection or treatment. The Hill equation provided a new approach for modelling gap detection ability.

Central Nervous System Trial Failures: Using the Fragile X Syndrome-mGluR5 Drug Target to Highlight the Complexities of Translating Preclinical Discoveries Into Human Trials.

Drug trials of the central nervous system(CNS) have been plagued with uninformative failures, often because of the difficulties of knowing definitively whether dosing achieved was sufficient to modulate the intended CNS target at adequate concentrations to produce pharmacodynamic or dose-related changes in readouts of brain function. Key design elements can be introduced into early-stage trials to get at this issue. This commentary builds on a review of earlier clinical studies in Fragile X syndrome to explore the extent to which the chain of evidence is in place to allow for interpretation of the results as ruling in or out the utility of modulating one or another molecular target to treat this disorder. Recent and current biomarker studies in Fragile X syndrome occurring subsequent to the clinical studies are reviewed to see if they might address any chain of evidence gaps. Despite the strong preclinical basis for targeting molecular mechanisms, the lack of efficacy seen in clinical studies remains uninterpretable, with regard to ruling in or out the utility of targeting the mechanism in a clinical population, given the absence of studies, which address whether doses of administered drug impacted the targeted brain mechanism. The value of pursuing clinical studies of compounds targeted to novel mechanisms in the absence of clinical pharmacological evidence of some anticipated mediating pharmacokinetic/pharmacodynamic signals is questionable. One or more biomarkers of a drug effect on brain function are needed to establish dose dependent CNS effects that allow one to interpret clinical results as ruling in or out a mechanism and providing a firm basis for continuing or not, as well as informing dose selection in any clinical efficacy trials. Initiatives to address this general need in pediatric psychopharmacology are highlighted.

MP49-15 OVERACTIVE BLADDER MEDICATION; HOW LONG SHOULD IT BE CONTINUED? - MIRABEGRON INTERFERES WITH CENTRAL SENSITIZATION IN A MOUSE MODEL OF OVERACTIVE BLADDER

You have accessJournal of UrologyCME1 May 2022MP49-15 OVERACTIVE BLADDER MEDICATION; HOW LONG SHOULD IT BE CONTINUED? - MIRABEGRON INTERFERES WITH CENTRAL SENSITIZATION IN A MOUSE MODEL OF OVERACTIVE BLADDER Joonbeom Kwon, Eun-Ju Lee, Hye-Ri Park, Hyun-Jung Cho, Ji-Ae Jang, Donghwi Park, and Naoki Yoshimura Joonbeom KwonJoonbeom Kwon More articles by this author , Eun-Ju LeeEun-Ju Lee More articles by this author , Hye-Ri ParkHye-Ri Park More articles by this author , Hyun-Jung ChoHyun-Jung Cho More articles by this author , Ji-Ae JangJi-Ae Jang More articles by this author , Donghwi ParkDonghwi Park More articles by this author , and Naoki YoshimuraNaoki Yoshimura More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002624.15AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The etiology of overactive bladder (OAB) is multifactorial, and bladder afferent hyperexcitability has been proposed to be one of the contributing factors. In addition, chronic afferent hyperexcitability may induce neural remodeling in the central nervous system (CNS). However, there has been no clear pathophysiologic evidence determining how long OAB treatments should be continued. We, therefore, investigated the CNS effect of mirabegron using an OAB animal model and compared the therapeutic effect between treatment cessation (CES) and continuation (CON) groups. METHODS: Female C57BL/6 mice were divided into 4 groups (N=8 in each): Sham, OAB, CES, and CON groups. OAB was induced by 3-times weekly intravesical instillations of KCl and hyaluronidase. Mirabegron (2mg/kg) was administered for 10 and 20 days in CES and CON groups, respectively. Cystometry was performed, and mRNA levels of bladder muscarinic, β-adrenergic, and P2X purinergic receptors were measured. CCL2 and CCR2 in L6-S1 dorsal root ganglia (DRG), as afferent markers, and CX3CR1, GFAP, and CCR2 in the L6 spinal cord, as markers of glial activation and central sensitization, were also evaluated by RT-PCR and immunohistology. RESULTS: OAB mice showed bladder overactivity and inefficient voiding (Fig 1-a) with increased M2, M3, P2X2, P2X3, P2X4, and P2X7 levels in the bladder and increased CCL2 and CCR2 in DRG, indicating afferent hyperexcitability (Fig 1-b). CX3CR1, GFAP, and CCR2 in the L6 spinal cord were upregulated in the OAB group (Fig 1-c). However, CON mice exhibited improvements of all these parameters of afferent hyperexcitability and central sensitization. Also, CON mice showed better voiding efficiency and reduced CNS changes compared with CES mice. CONCLUSIONS: Central sensitization may be an important pathophysiological mechanism of OAB. Continuous treatment of OAB with mirabegron seems to prevent the process of central sensitization via improvement of CNS neural remodeling. Therefore, continuous OAB medication may be desirable for long-term disease control. Source of Funding: Astellas Pharma. Co.Ltd. (ISR005728) © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e859 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joonbeom Kwon More articles by this author Eun-Ju Lee More articles by this author Hye-Ri Park More articles by this author Hyun-Jung Cho More articles by this author Ji-Ae Jang More articles by this author Donghwi Park More articles by this author Naoki Yoshimura More articles by this author Expand All Advertisement PDF DownloadLoading ...

Pep19 Has a Positive Effect on Insulin Sensitivity and Ameliorates Both Hepatic and Adipose Tissue Phenotype of Diet-Induced Obese Mice.

Peptide DIIADDEPLT (Pep19) has been previously suggested to improve metabolic parameters, without adverse central nervous system effects, in a murine model of diet-induced obesity. Here, we aimed to further evaluate whether Pep19 oral administration has anti-obesogenic effects, in a well-established high-fat diet-induced obesity model. Male Swiss mice, fed either a standard diet (SD) or high-fat diet (HFD), were orally administrated for 30 consecutive days, once a day, with saline vehicle or Pep19 (1 mg/kg). Next, several metabolic, morphological, and behavioral parameters were evaluated. Oral administration of Pep19 attenuated HFD body-weight gain, reduced in approximately 40% the absolute mass of the endocrine pancreas, and improved the relationship between circulating insulin and peripheral insulin sensitivity. Pep19 treatment of HFD-fed mice attenuated liver inflammation, hepatic fat distribution and accumulation, and lowered plasma alanine aminotransferase activity. The inguinal fat depot from the SD group treated with Pep19 showed multilocular brown-fat-like cells and increased mRNA expression of uncoupling protein 1 (UCP1), suggesting browning on inguinal white adipose cells. Morphological analysis of brown adipose tissue (BAT) from HFD mice showed the presence of larger white-like unilocular cells, compared to BAT from SD, Pep19-treated SD or HFD mice. Pep19 treatment produced no alterations in mice behavior. Oral administration of Pep19 ameliorates some metabolic traits altered by diet-induced obesity in a Swiss mice model.

Intravitreal Injection of PACAP Attenuates Acute Ocular Hypertension-Induced Retinal Injury Via Anti-Apoptosis and Anti-Inflammation in Mice.

PurposePituitary adenylate cyclase-activating polypeptide (PACAP) has shown potent neuroprotective effects in central nervous system and retina disorders. However, whether PACAP can attenuate retinal neurodegeneration induced by acute ocular hypertension (AOH) and the underlying mechanisms remain unknown. In this study, we aimed to investigate the effects of PACAP on the survival and function of retinal ganglion cells (RGCs), apoptosis, and inflammation in a mouse model of AOH injury.MethodsPACAP was injected into the vitreous body immediately after inducing AOH injury. Hematoxylin and eosin staining and optical coherence tomography were used to evaluate the loss of retina tissue. Pattern electroretinogram was used to evaluate the function of RGCs. TUNEL assay was used to detect apoptosis. Immunofluorescence and western blot were employed to evaluate protein expression levels.ResultsPACAP treatment significantly reduced the losses of whole retina and inner retina thicknesses, Tuj1-positive RGCs, and the amplitudes of pattern electroretinograms induced by AOH injury. Additionally, PACAP treatment remarkably reduced the number of TUNEL-positive cells and inhibited the upregulation of Bim, Bax, and cleaved caspase-3 and downregulation of Bcl-xL after AOH injury. Moreover, PACAP markedly inhibited retinal reactive gliosis and vascular inflammation, as demonstrated by the downregulation of GFAP, Iba1, CD68, and CD45 in PACAP-treated mice. Furthermore, upregulated expression of NF-κB and phosphorylated NF-κB induced by AOH injury was attenuated by PACAP treatment.ConclusionsPACAP could prevent the loss of retinal tissue and improve the survival and function of RGCs. The neuroprotective effect of PACAP is probably associated with its potent anti-apoptotic and anti-inflammatory effects.

Effect of siponimod on magnetic resonance imaging measures of neurodegeneration and myelination in secondary progressive multiple sclerosis: Gray matter atrophy and magnetization transfer ratio analyses from the EXPAND phase 3 trial

Background: Magnetic resonance imaging (MRI) measurements of gray matter (GM) atrophy and magnetization transfer ratio (MTR; correlate of myelination) may provide better insights than conventional MRI regarding brain tissue integrity/myelination in multiple sclerosis (MS). Objective: To examine the effect of siponimod in the EXPAND trial on whole-brain and GM atrophy, newly formed normalized magnetization transfer ratio (nMTR) lesions, and nMTR-assessed integrity of normal-appearing brain tissue (NABT), cortical GM (cGM), and normal-appearing white matter (NAWM). Methods: Patients with secondary progressive multiple sclerosis (SPMS) received siponimod (2 mg/day; n =1037) or placebo (n = 523). Endpoints included percentage change from baseline to months 12/24 in whole-brain, cGM, and thalamic volumes; change in nMTR from baseline to months 12/24 in NABT, cGM, and NAWM; MTR recovery in newly formed lesions. Results: Compared with placebo, siponimod significantly reduced progression of whole-brain and GM atrophy over 12/24 months, and was associated with improvements in brain tissue integrity/myelination within newly formed nMTR lesions and across NABT, cGM, and NAWM over 24 months. Effects were consistent across age, disease duration, inflammatory activity subgroups, and disease severity. Conclusion: Siponimod reduced brain tissue damage in patients with SPMS as evidenced by objective measures of brain tissue integrity/myelination. This is consistent with central nervous system (CNS) effects observed in preclinical models. ClinicalTrials.gov number: NCT01665144.

Safety and Tolerability of Fesoterodine in Older Adult Patients with Overactive Bladder

BackgroundOlder patients (> 65 yr) suffering from overactive bladder (OAB) are more likely to have functional impairment and comorbidity than those without OAB. This article reviews available published studies and discusses how fesoterodine might meet the specific needs of the older OAB patient.MethodsA comprehensive literature search was undertaken in order to evaluate fesoterodine safety in older OAB patients.ResultsFesoterodine offers flexible dosing, allowing the clinician to balance risk and benefits according to the symptoms and preferences of the patient. Its balanced affinity for M2 and M3 muscarinic receptors may lead to its benefit on OAB symptoms. Its active metabolite is a P-gp substrate that is actively transported from the central nervous system (CNS), potentially avoiding adverse CNS effects. Fesoterodine can be used in mild or moderate hepatic or renal insufficiency and no dose adjustment is routinely required. Fesoterodine’s benefit has been demonstrated in multiple clinical trials in older and medically vulnerable patients. Fesoterodine was rated as “beneficial” in the LUTS-FORTA classification due to its efficiency and tolerability in older patients.ConclusionHere, the use of fesoterodine in older and vulnerable patients is summarized given the need to approach pharmacotherapy for OAB differently in older adults.

Role of the arterial baroreflex in the sympathetic response to hyperinsulinemia in adult humans.

Muscle sympathetic nerve activity (MSNA) increases during hyperinsulinemia, primarily attributed to central nervous system effects. Whether peripheral vasodilation induced by insulin further contributes to increased MSNA via arterial baroreflex-mediated mechanisms requires further investigation. Accordingly, we examined baroreflex modulation of the MSNA response to hyperinsulinemia. We hypothesized that rescuing peripheral resistance with coinfusion of the vasoconstrictor phenylephrine would attenuate the MSNA response to hyperinsulinemia. We further hypothesized that the insulin-mediated increase in MSNA would be recapitulated with another vasodilator (sodium nitroprusside, SNP). In 33 young healthy adults (28 M/5F), MSNA (microneurography) and arterial blood pressure (BP, Finometer/brachial catheter) were measured, and total peripheral resistance (TPR, ModelFlow) and baroreflex sensitivity were calculated at rest and during intravenous infusion of insulin (n = 20) or SNP (n = 13). A subset of participants receiving insulin (n = 7) was coinfused with phenylephrine. Insulin infusion decreased TPR (P = 0.01) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity or BP (P > 0.05). Coinfusion with phenylephrine returned TPR and MSNA to baseline, with no effect on arterial baroreflex sensitivity (P > 0.05). Similar to insulin, SNP decreased TPR (P < 0.02) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity (P > 0.12). Acute hyperinsulinemia shifts the baroreflex stimulus-response curve to higher MSNA without changing sensitivity, likely due to insulin's peripheral vasodilatory effects. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.NEW & NOTEWORTHY We hypothesized that elevation in muscle sympathetic nervous system activity (MSNA) during hyperinsulinemia is mediated by its peripheral vasodilator effect on the arterial baroreflex. Using three separate protocols in humans, we observed increases in both MSNA and cardiac output during hyperinsulinemia, which we attributed to the baroreflex response to peripheral vasodilation induced by insulin. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.

ATP-sensitive Potassium Channel Subunits in Neuroinflammation: Novel Drug Targets in Neurodegenerative Disorders.

Arachidonic acids and its metabolites modulate plenty of ligand-gated, voltage-dependent ion channels, and metabolically regulated potassium channels including ATP-sensitive potassium channels (KATP). KATP channels are hetero-multimeric complexes of sulfonylureas receptors (SUR1, SUR2A or SUR2B) and the pore-forming subunits (Kir6.1 and Kir6.2) likewise expressed in the pre-post synapsis of neurons and inflammatory cells, thereby affecting their proliferation and activity. KATP channels are involved in amyloid-β (Aβ)-induced pathology, therefore emerging as therapeutic targets against Alzheimer's and related diseases. The modulation of these channels can represent an innovative strategy for the treatment of neurodegenerative disorders; nevertheless, the currently available drugs are not selective for brain KATP channels and show contrasting effects. This phenomenon can be a consequence of the multiple physiological roles of the different varieties of KATP channels. Openings of cardiac and muscular KATP channel subunits, are protective against caspase-dependent atrophy in these tissues and some neurodegenerative disorders, whereas in some neuroinflammatory diseases, benefits can be obtained through the inhibition of neuronal KATP channel subunits. For example, glibenclamide exerts an anti-inflammatory effect in respiratory, digestive, urological, and central nervous system (CNS) diseases, as well as in ischemia-reperfusion injury associated with abnormal SUR1-Trpm4/TNF-α or SUR1-Trpm4/ Nos2/ROS signaling. Despite this strategy being promising, glibenclamide may have limited clinical efficacy due to its unselective blocking action of SUR2A/B subunits also expressed in cardiovascular apparatus with pro-arrhythmic effects and SUR1 expressed in pancreatic beta cells with hypoglycemic risk. Alternatively, neuronal selective dual modulators showing agonist/antagonist actions on KATP channels can be an option.