Peripheral Side Effects Research Articles

Because of γ-Aminobutyric Acid-Glutamate Imbalance, Gut Microbiota, or Both? Delirious Mania Induced by Ciprofloxacin Use: A Case Report and Review of the Literature.

Ciprofloxacin is an antibiotic from the fluoroquinolone group that is frequently used in many clinical practices. In addition to its peripheral neuropathic side effects, it is an antibiotic that can pass through the blood-brain barrier due to its lipophilic features and cause rare central nervous system symptoms. Although cases of neuropsychiatric symptoms developing after treatment with ciprofloxacin have been reported in the literature, the number of reports of manic episodes after ciprofloxacin use is limited, and there have been no reports of delirious mania developing after ciprofloxacin use until the case presented in this report. Here we report the case of a 52-year-old woman who developed manic symptoms after receiving ciprofloxacin, which evolved into delirious mania. Clinical factors that may predispose to neurotoxicity are discussed and compared with features of the mania cases in the literature. The underlying neurobiological mechanisms are also reviewed.

Potential Regulation of the Long Non-Coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript1 by Estrogen in Parkinson’s Disease

Parkinson’s disease (PD) is the second-leading cause of death among neurodegenerative disease after Alzheimer’s disease (AD), affecting around 2% of the population. It is expected that the incidence of PD will exceed 12 million by 2040. Meanwhile, there is a recognized difference in the phenotypical expression of the disease and response to treatment between men and women. Men have twice the incidence of PD compared to women, who have a late onset and worse prognosis that is usually associated with menopause. In addition, the incidence of PD in women is associated with the cumulative estrogen levels in their bodies. These differences are suggested to be due to the protective effect of estrogen on the brain, which cannot be given in clinical practice to improve the symptoms of the disease because of its peripheral side effects, causing cancer in both males and females in addition to the feminizing effect it has on males. As PD pathophysiology involves alteration in the expression levels of multiple LncRNAs, including metastatic-associated lung adenocarcinoma transcript 1 (MALAT1), and as estrogen has been illustrated to control the expression of MALAT1 in multiple conditions, it is worth investigating the estrogen–MALAT1 interaction in Parkinson’s disease to mimic its protective effect on the brain while avoiding its peripheral side effects. The following literature review suggests the potential regulation of MALAT1 by estrogen in PD, which would enhance our understanding of the pathophysiology of the disease, improving the development of more tailored and effective treatments.

Beyond the blur: Scopolamine's utility and limits in modeling cognitive disorders across sexes - Narrative review.

Scopolamine, widely regarded as the gold standard in preclinical studies of memory impairments, acts as a non-selective antagonist of central and peripheral muscarinic receptors. While its application in modeling dementia primarily involves antagonism at the M1 receptor, its non-selective peripheral actions may introduce adverse effects that influence behavioral test outcomes. This review analyzes preclinical findings to consolidate knowledge on scopolamine's use and elucidate potential mechanisms responsible for its amnestic effects. We focused on recognition, spatial, and emotional memory processes, alongside executive functions such as attention, cognitive flexibility, and working memory. The cognitive effects of scopolamine are highly dose-dependent, influenced by factors such as species, age, and sex of subjects. Notably, scopolamine rapidly induces observable memory impairments across species, from fish to rodents and primates, often with deficits that can persist for days. However, the compound's broad action on muscarinic receptors and its peripheral side effects, including pupil dilation and reduced salivation, complicates result interpretation, particularly in tasks requiring visual discrimination or food intake. The review also highlights scopolamine's translational value in modeling dementia and Alzheimer's disease, emphasizing the importance of considering individual factors and task-specific designs. Despite its widespread use, scopolamine's limited specificity for cholinergic dysfunction and inability to fully mimic the complex pathophysiology of cognitive disorders like Alzheimer's and Parkinson's disease point to the need for complementary models. This review aims to guide researchers in using scopolamine for modeling cognitive impairments, ensuring attention to factors impacting experimental outcomes.

IUPHAR Review on muscarinic M1 and M4 receptors as drug treatment targets relevant to the molecular pathology of schizophrenia.

Cobenfy, a co-formulation of xanomeline and trospium, is the first drug not acting on the dopaminergic system of the CNS approved for the treatment of schizophrenia by the FDA. Xanomeline is a muscarinic M1 and M4 receptor (CHRM1 and CHRM4) agonist whilst trospium is a peripherally active CHRM antagonist that reduces the unwanted peripheral side-effects of xanomeline. Relevant to this exciting development, this review details the human CNS cholinergic systems and how those systems are affected by the molecular pathology of schizophrenia in a way suggesting activating the CHRM1 and 4 would be beneficial in treating the disorder. The CNS distribution of CHRMs is presented along with findings using CHRM knockout mice and mice treated with drugs that activate the CHRM1 and / or M4, these data explain why these CHRMs could be involved in the genesis of the symptoms of schizophrenia. Next, the process leading to the formulation of Cobenfy and the preclinical data on xanomeline are reviewed showing why Cobenfy was expected to be useful in treating schizophrenia. The pipeline of drugs targeting CHRM1 and /or M4 receptors to treat schizophrenia are discussed. Finally, the molecular pathology of two sub-groups within schizophrenia, separated based on the presence or absence of a deficit of cortical CHRM1, are reviewed to show how such approaches could identify new drug targets. In conclusion, the history of the development of Cobenfy highlights how a growing understanding the pathophysiology of schizophrenia will suggest new treatment targets for the disorder and that pharmacologists can synthesise drugs to target these sites.

Preparation and characterization of poly(ethylene glycol)-b-poly(tert-butyl methacrylate) micelles as potential nanocarriers for donepezil

Polymeric micelles were prepared for the delivery of donepezil, a leading Alzheimer’s disease drug, to enhance its transport across the blood–brain barrier (BBB). Poly(ethylene glycol)-b-poly(tert-butyl methacrylate) amphiphilic block copolymers were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. The polymers were characterized by gel permeation chromatography and nuclear magnetic resonance spectroscopy. Empty and donepezil loaded polymer micelles were formed using the dialysis method and characterized by dynamic light scattering and transmission electron microscopy. Drug loading efficiency and release behavior were monitored using UV/Vis spectroscopy, and cytotoxicity was evaluated via colorimetric tests and impedance measurements. Additionally, the permeability of the nanocarriers across an in vitro BBB culture model was assessed. Drug-loaded micelles demonstrated similar permeability to free donepezil but offered sustained release and improved stability. This micellar delivery system holds significant potential for improving therapeutic outcomes in Alzheimer’s treatment by enhancing donepezil’s delivery across the BBB. Improved BBB permeability and sustained drug release could lead to more effective concentration of the drug in the brain, potentially reducing peripheral cholinergic side effects, such as nausea and vomiting, often observed with traditional donepezil administration. This could result in better patient compliance and improved cognitive outcomes, making this nanocarrier system a promising alternative for Alzheimer’s therapy.

Human cell surface-AAV interactomes identify LRP6 as blood-brain barrier transcytosis receptor and immune cytokine IL3 as AAV9 binder

Adeno-associated viruses (AAVs) are foundational gene delivery tools for basic science and clinical therapeutics. However, lack of mechanistic insight, especially for engineered vectors created by directed evolution, can hamper their application. Here, we adapt an unbiased human cell microarray platform to determine the extracellular and cell surface interactomes of natural and engineered AAVs. We identify a naturally-evolved and serotype-specific interaction between the AAV9 capsid and human interleukin 3 (IL3), with possible roles in host immune modulation, as well as lab-evolved low-density lipoprotein receptor-related protein 6 (LRP6) interactions specific to engineered capsids with enhanced blood-brain barrier crossing in non-human primates after intravenous administration. The unbiased cell microarray screening approach also allows us to identify off-target tissue binding interactions of engineered brain-enriched AAV capsids that may inform vectors’ peripheral organ tropism and side effects. Our cryo-electron tomography and AlphaFold modeling of capsid-interactor complexes reveal LRP6 and IL3 binding sites. These results allow confident application of engineered AAVs in diverse organisms and unlock future target-informed engineering of improved viral and non-viral vectors for non-invasive therapeutic delivery to the brain.

P20: Evaluating xanomeline and trospium as a treatment for psychosis associated with Alzheimer’s disease: design of the phase 3, ADEPT-1, relapse prevention study

Background: There are no approved treatments for Alzheimer’s disease psychosis (ADP). Xanomeline, a brain- penetrant M1/M4 preferring muscarinic receptor agonist, showed antipsychotic efficacy in placebo-controlled trials in subjects with AD [Bodick NC et al. 1997; DOI: 10.1001/archneur.1997.00550160091022]. Despite promising efficacy, further development of xanomeline was limited by cholinergic adverse events. The investigational antipsychotic xanomeline and trospium combines xanomeline with trospium, an FDA-approved muscarinic receptor antagonist that does not measurably cross the blood-brain barrier. Trospium acts to mitigate the peripheral procholinergic side effects of xanomeline, providing a strategy for using xanomeline to stimulate brain muscarinic receptors with a decreased side effect burden. Unlike available antipsychotics, xanomeline and trospium have no direct dopamine D2-blocking activity, and as such, its safety and tolerability profile is different.Methods: The phase 3 ADEPT-1 trial is a double-blind, flexible-dose, placebo-controlled randomized withdrawal study to evaluate the safety and efficacy of xanomeline and trospium in decreasing the risk of relapse in subjects with ADP. Subjects aged 55-90 years with moderate to severe psychosis associated with mild to severe AD (Mini- Mental State Exam score range 8-22) will be enrolled into the study. Subjects will receive single-blind xanomeline and trospium for 12 weeks. Each subject will be flexibly titrated to the maximum dose of xanomeline and trospium 200 mg xanomeline/20 mg trospium/day. At the end of the single-blind treatment, eligible responders will be randomized to either continue xanomeline and trospium or be switched to matched placebo for a 26-week double- blind treatment period. A responder is defined as a subject with a ≥40% decrease (improvement) on the Neuropsychiatric Inventory- Clinician: Hallucinations + Delusions (NPI-C: H+D) score compared with baseline (day 1) and a Clinician Global Impression–Change (CGI-C) score of 1 or 2 (very much improved or improved).Results: The primary endpoint of the study, time from randomization to relapse during the double-blind, randomized withdrawal treatment, will be evaluated by survival analysis using Kaplan-Meier Methods. The study started in August 2022 and will randomize approximately 200 subjects.Conclusions: The trial design of the ADEPT-1 study is an efficient way to assess the potential for xanomeline and trospium to provide clinically meaningful benefit in preventing the return of ADP in patients who have responded to xanomeline and trospium.

Antibody conjugated targeted nanotherapy epigenetically inhibits calpain-mediated mitochondrial dysfunction to attenuate Parkinson’s disease

Many neurodegenerative and psychiatric malignancies like Parkinson’ disease (PD) originate from an imbalance of 17β-Estradiol (E2) in the human brain. However, the peripheral side effects of the usage of E2 for PD therapy and less understanding of the molecular mechanism hinder establishing its neurotherapeutic potential. In the present work, systemic side effects were overcome by targeted delivery using Dopamine receptor D3 (DRD3) conjugated E2-loaded chitosan nanoparticles (Ab-ECSnps) that showed a promising delivery to the brain. E2 is a specific calpain inhibitor that fosters neurodegeneration by disrupting mitochondrial function, while B-cell-specific Moloney murine leukemia virus integration region 1 (BMI1), an epigenetic regulator, is crucial in preserving mitochondrial homeostasis. We showed the administration of Ab-ECSnps inhibits calpain's translocation into mitochondria while promoting the translocation of BMI1 to mitochondria, thereby conferring neurotherapeutic benefits by enhancing cell viability, increasing mitochondrial DNA copy number, and preserving mitochondrial membrane potential. Further, we showed a novel molecular mechanism of BMI1 regulation by calpain that might contribute to maintaining mitochondrial homeostasis for attenuating PD. Concomitantly, Ab-ECSnps showed neurotherapeutic potential in the in vivo PD model. We showed for the first time that our brain-specific targeted delivery might regulate calpain-mediated BMI1 expression, thereby preserving mitochondrial homeostasis to alleviate PD.

Anticholinerge lading bij oudere volwassenen in een woonzorgcentrum: een pilootonderzoek

Older adults are more at risk for side effects from medications. Mainly anticholinergic side effects can lead to central and peripheral side effects on somatic and cognitive levels. In this study, we determined the anticholinergic load of the medication regimens of residents of a residential care center using two validated measurement scales. We also examined to which extent the class(es) of medications influence this anticholinergic load. Finally, we analyzed the association of a high anticholinergic load with incidents (urinary tract infections, falls, delirium). In this pilot study we see a high degree of polymedication and use of psychotropic drugs with an anticholinergic effect. On average we established a score of 1.67 on the ACB and a score of 0.87 on the DBI. The anticholinergic load in the ACB is mainly determined by antipsychotics (t = 6.110, p < 0.001), in the DBI an influence of all medications with anticholinergic properties is seen (F = 6.764, p < 0.001). A risk score on the DBI has a statistically significant correlation with experiencing a urinary tract infection (F = 5.877, p = 0.018). This influence remains significant after adjusting for covariates. The anticholinergic load of medication regimens in residents is high. An increased anticholinergic load is also associated with urinary tract infection. Reducing the anticholinergic load within residential care centers therefore represents an important challenge for the future.

Treat the individual and not the angle.

Glaucoma, the silent thief of sight, is one of the most common vision-threatening conditions. Even though POAG (primary open angle glaucoma) is more common, PACG (primary angle closure glaucoma) is the dreaded variant. ISGEO (International Society for Geographical and Epidemiological Ophthalmology) has classified primary angle closure as PACS (primary angle closure suspect), PAC (primary angle closure), and PACG (primary angle closure glaucoma. The inconspicuous nature of PACS makes its diagnosis and treatment very tricky. To determine which cases are best suited for laser peripheral iridotomy. Laser peripheral iridotomy is the gold standard for acute primary angle closure glaucoma treatment. But there is a lot of confusion regarding its use in PACS as a prophylactic measure. We have tried to throw light on laser peripheral iridotomy, a much debatable topic. The video focuses on various trials regarding laser peripheral iridotomy, the indications, side effects, and contraindications. We have also discussed its use as a therapeutic and prophylactic procedure. The video highlights that the approach of laser peripheral iridotomy should be on a case-by-case basis. https://youtu.be/kiEYI9ct2Oo.

Novel ligand conjugated poly(propylene imine) dendrimers for brain targeted delivery of tacrine hydrochloride

Alzheimer's disease (AD) is the most common type of neurodegenerative disorder characterized by extracellular deposition of Amyloid β and intracellular deposition of neurofibrillary tangles. One of the most common etiological factors is rapid and excessive hydrolysis of acetylcholine by acetylcholinesterase (AChE) enzyme. Tacrine is one of the most potent and first USFDA approved centrally acting AChE inhibitor recommended for treatment of AD, but it is no longer in use as it causes severe peripheral side effects, mainly hepatotoxicity. In this research work, novel dendrimeric conjugates were developed with an aim of enhancing the brain targeting efficiency of tacrine and eliminating the peripheral side effects. Poly(propyleneimine) G5.0 dendrimers were conjugated with oleic acid as a brain targeting ligand, and the conjugation was confirmed by Fourier-transform infrared spectroscopy, 1H nuclear magnetic resonance spectroscopy and dynamic light scattering studies. Tacrine hydrochloride was loaded into the plain dendrimer as well as oleic acid conjugated dendrimer by physical encapsulation method. The in vitro AChE inhibitory study showed retention of the AChE inhibition ability of tacrine in dendrimeric conjugates. The safety of the drug loaded conjugates was confirmed by haemolytic, nasal ciliotoxicity and cytotoxicity studies. Further, cellular uptake studies in SH-SY5Y cells showed abundance of green cytoplasmic fluorescence, suggesting enhanced internalization of dendrimeric conjugates. The results of this research work support the further exploration of this novel dendrimers based conjugated delivery system for in vivo studies as a potential alternative to treat AD.

Intranasal administration of sertraline ensures sustained brain delivery and antidepressant effect in a mouse model of depression

The pursuit of more potent and efficacious antidepressant therapies is of utmost significance. Herein, the intranasal (IN) route was investigated for sertraline brain delivery, encompassing a comparative pharmacokinetic study after a single-dose administration to mice by IN, intravenous (IV) (4.87 mg/kg) and oral (10 mg/kg) routes, and an efficacy/toxicity study to explore the therapeutic effect in mice subjected to the unpredictable chronic mild stress (UCMS) protocol. Neurotransmitters and melatonin were quantified in prefrontal cortex and plasma, respectively. A different drug biodistribution behavior was unveiled for a CNS-acting drug administered by means of the IN route. For the first time, IN administration of sertraline exhibited heightened systemic exposure (bioavailability = 166 %), and a sustained drug release into the brain, in opposition to IV and oral routes, avoiding drug fluctuation. The lower lung exposition (given by normalized area under the curve) observed after IN instillation envisions the reduction of sertraline pulmonary side effects and similarly other peripheral side effects. IN sertraline treatment displayed significant efficacy in ameliorating anhedonia after one week of administration while the 14-day IN treatment regimen translated into decreased immobility time and increased swimming time in the forced swimming test, suggesting an improvement of the depressive-like behavior displayed by the animal depressive-model. Remarkably, these effects were absent with oral sertraline, despite the higher used dose. Noteworthy neurotransmitter alterations were observed, with IN sertraline markedly reducing adrenaline in the prefrontal cortex, while serotonin and melatonin increased following both administration routes. With its sustained brain delivery and serotonin- and melatonin-enhancing potential, the innovative strategy of IN sertraline holds the potential not only to effectively address depressive symptoms but also to mitigate challenges inherent to classic treatments.

Evodiamine attenuates oxidative stress and ferroptosis by inhibiting the MAPK signaling to improve bortezomib-induced peripheral neurotoxicity.

Bortezomib (BTZ) is a commonly used antitumor drug, but its peripheral neuropathy side effect poses a limitation on its dosage. Evodiamine (EVO) exhibits various biological activities, including antioxidant, anti-inflammatory, and anticancer effects. The purpose of this investigation is to confirm the impact of EVO on BTZ-induced peripheral neurotoxicity. GeneCards and HERB were applied to analyze the targets of peripheral neurotoxicity and EVO. The Gene Ontology (GO)and Kyoto Encyclopedia of Genes and Genomes (KEGG)pathways enrichment analysis of the hub genes were identified by DAVID. Rat dorsal root ganglion neurons (DRGs) and rat RSC96 Schwann cells (SCs) were treated with BTZ to simulate peripheral neurotoxicity. BTZ-induced peripheral neurotoxicity was assessed by detecting cell viability, proliferation, oxidative stress, and ferroptosis in DRGs and SCs. The mitogen-activated protein kinase (MAPK) signaling was scrutinized by Western blot assay. The Venn diagram for the overlapping targets of EVO and peripheral neurotoxicity showed that EVO might regulate peripheral neurotoxicity by influencing cell oxidative stress, ferroptosis, and MAPK signaling pathway. EVO attenuated BTZ-induced toxicity in DRGs and SCs. EVO attenuated BTZ-induced oxidative stress damage in DRGs and SCs by reducing reactive oxygen species and malondialdehyde levels and enhancing glutathione level. EVO attenuated BTZ-induced ferroptosis in DRGs and SCs. EVO inhibited BTZ-induced activation of the MAPK signaling in DRGs and SCs. Activation of the MAPK signaling reversed the neuroprotective effect of EVO on BTZ-induced oxidative stress injury and ferroptosis. EVO attenuated oxidative stress and ferroptosis by inhibiting the MAPK signaling to improve BTZ-induced peripheral neurotoxicity.

Methamphetamine (MA) use and MA-induced psychosis are associated with increasing aberrations in the compensatory immunoregulatory system, interleukin-1α, and CCL5 levels

There are only a few studies reporting on the immunological profiles of methamphetamine (MA) use, MA dependency, or MA-induced psychosis (MAP). This study measured M1 macrophage, T helper (Th)-1, Th-2, growth factor, and chemokine profiles, as well as the immune inflammatory response system (IRS) and compensatory immunoregulatory system (CIRS) in peripheral blood samples from patients with MA use (n = 51), MA dependence (n = 47), and MAP (n = 43) in comparison with controls (n = 32). We discovered that persistent MA use had a robust immunosuppressive impact on all immunological profiles. The most reliable biomarker profile of MA use is the combination of substantial CIRS suppression and a rise in selected pro-inflammatory cytokines, namely CCL27 (CTACK), CCL11 (eotaxin), and interleukin (IL)-1α. In addition, MA dependency is associated with increased immunosuppression, as demonstrated by lower stem cell factor levels and higher IL-10 levels. MAP is related to a significant decrease in all immunological profiles, particularly CIRS, and an increase in CCL5 (RANTES), IL-1α, and IL-12p70 signaling. In conclusion, long-term MA use and dependency severely undermine immune homeostasis, whereas MAP may be the consequence of increased IL-1α – CCL5 signaling superimposed on strongly depleted CIRS and Th-1 functions. The widespread immunosuppression established in longstanding MA use may increase the likelihood of infectious and immune illness or exacerbate disorders such as hepatitis and AIDS. Furthermore, elevated levels of CCL5, CCL11, CCL27, IL-1α, and/or IL-12p70 may play a role in the peripheral (atherosclerosis, cutaneous inflammation, immune aberrations, hypospermatogenesis) and central (neuroinflammation, neurotoxic, neurodegenerative, depression, anxiety, and psychosis) side effects of MA use.

Polysorbate 80 surface modified SLNs of formoterol suppress SNCA gene and mitochondrial oxidative stress in mice model of Parkinson’s disease

The present study hypothesises that the selective brain β2 receptor activation through β2-adrenoreceptor agonist (β2ARA), Formoterol (FMT), suppresses SNCA gene expression, a pathological hallmark of Parkinson’s disease (PD) in brain. Further, it is also hypothesized that brain targeted delivery of Formoterol via polysorbate-80 surface modified solid lipid nanoparticles of Formoterol (FMT-SLNs-PS80) can improve its stability, therapeutic efficacy and avoid/reduce peripheral off-target side effects. FMT-SLNs-PS80 was prepared by solvent injection method, the formulation was optimized by using Box–Behnken design and characterized by measuring drug content, entrapment efficacy, particle size, zeta potentials and poly dispersibility. The FMT-SLNs-PS80, significantly decreases the SNCA expression, mitochondrial membrane damage and rotenone induced changes in oxidative (SOD, CAT, GSH and ROS) stress markers in SH-SY5Y cell lines. The ex vivo permeation study of the formulation using everted chicken ileum exhibited a steady state flux. The pharmacokinetic and tissue distribution studies of the formulation in rats showed a significant improvement in the kinetic parameters when compared to naïve FMT, further the formulation also improved the brain bioavailability of FMT. The anti-Parkinson’s efficacy studies of the formulation in mice showed a significant neuroprotection against rotenone-induced changes in behavioural and biochemical parameters. Further, the histopathological analysis of mice brain confirms a significant neuroprotective benefit. The present study successfully establishes the brain targeted delivery and anti-Parkinson’s therapeutic efficacy of FMT-SLNs-PS80.

Synthesis of an insulin-loaded mucoadhesive nanoparticle designed for intranasal administration: focus on new diffusion media.

Intranasal administration is a drug delivery approach to provide a non-invasive pharmacological response in the central nervous system with relatively small peripheral side effects. To improve the residence time of intranasal drug delivery systems in the nasal mucosa, mucoadhesive polymers (e.g., chitosan) can be used. Here, insulin-loaded chitosan nanoparticles were synthesized and their physiochemical properties were evaluated based on requirements of intranasal administration. The nanoparticles were spherical (a hydrodynamic diameter of 165.3nm, polydispersity index of 0.24, and zeta potential of +21.6mV) that granted mucoadhesion without any noticeable toxicity to the nasal tissue. We applied a new approach using the Krebs-Henseleit buffer solution along with simulated nasal fluid in a Franz's diffusion cell to study this intranasal drug delivery system. We used the Krebs-Henseleit buffer because of its ability to supply glucose to the cells which serves as a novel ex vivo diffusion medium to maintain the viability of the tissue during the experiment. Based on diffusion rate and histopathological endpoints, the Krebs-Henseleit buffer solution can be a substituent solution to the commonly used simulated nasal fluid for such drug delivery systems.

Outcomes and clinical implications of intranasal insulin on cognition in humans: A systematic review and meta-analysis.

Aberrant brain insulin signaling has been posited to lie at the crossroads of several metabolic and cognitive disorders. Intranasal insulin (INI) is a non-invasive approach that allows investigation and modulation of insulin signaling in the brain while limiting peripheral side effects. The objective of this systematic review and meta-analysis is to evaluate the effects of INI on cognition in diverse patient populations and healthy individuals. MEDLINE, EMBASE, PsycINFO, and Cochrane CENTRAL were systematically searched from 2000 to July 2021. Eligible studies were randomized controlled trials that studied the effects of INI on cognition. Two independent reviewers determined study eligibility and extracted relevant descriptive and outcome data. Twenty-nine studies (pooled N = 1,726) in healthy individuals as well as those with Alzheimer's disease (AD)/mild cognitive impairment (MCI), mental health disorders, metabolic disorders, among others, were included in the quantitative meta-analysis. Patients with AD/MCI treated with INI were more likely to show an improvement in global cognition (SMD = 0.22, 95% CI: 0.05-0.38 p = <0.00001, N = 12 studies). Among studies with healthy individuals and other patient populations, no significant effects of INI were found for global cognition. This review demonstrates that INI may be associated with pro-cognitive benefits for global cognition, specifically for individuals with AD/MCI. Further studies are required to better understand the neurobiological mechanisms and differences in etiology to dissect the intrinsic and extrinsic factors contributing to the treatment response of INI.

Discovery of thiazole salt AChE inhibitors and development of thiamine disulfide prodrugs targeting the central nervous system

The selective AChE inhibitor donepezil has been approved by the FDA as a first-line drug for the treatment of mild to moderate AD. However, many peripheral side effects were observed in patients taking donepezil. Our main objective here is to provide insight into the opportunities and challenges associated with development of AChE inhibitors with high brain exposure and low peripheral side effects. In this study, we have for the first time revealed a series of novel thiazole salt AChE inhibitors, which exhibit a nanomolar inhibitory effect on human AChE. We further developed thiamine disulfide prodrugs based on optimized thiazole salt AChE inhibitors, which are reduced in the brain to form thiazole salt AChE inhibitors. In vivo experiments have confirmed that the representative prodrug Tap4 (i.p., 10 mg/kg) can be converted into the thiazole salt AChE inhibitor Tat2 and shows high brain exposure, reaching 500 ng/g. Further, the inhibitory effect of the prodrug Tap4 on AChE is obviously stronger in the brain than that on intestinal AChE of ICR mice. Our study provides a possible basis for centrally targeted thiazole salt inhibitors in the treatment of neurodegenerative diseases.

Effect of multiple-dose regimens of cyclooxygenase inhibitors and their combinations with mexidol on behavior in mature rats

Effects of multiple-dose regimens (oral, daily, once a day for 15 days) of cyclooxygenase (COX) inhibitors etoricoxib (1 and 10 mg/kg), diclofenac sodium (1 and 5 mg/kg) and their combinations with 2-ethyl-6-methyl-3-hydroxypyridine succinate (mexidol 25 mg/kg) on rat behavior were studied in the open field test, rotarod test and elevated plus maze test. Exploratory (in open field test) and locomotor (in rotarod test) behavior of rats was significantly weakened only by the non-selective COX inhibitor diclofenac sodium at 5 mg/kg, which is due to the peripheral side effect of the drug. The selective COX-2 inhibitor etoricoxib increased the time in the central area of the elevated plus maze at 1 and 10 mg/kg and reduced the latent period of locomotion in the open field test at 10 mg/kg. A combination of diclofenac sodium (1 mg/kg) with mexidol neither reduced exploratory behavior nor caused motor deficit in contrast to diclofenac sodium at 5 mg/kg. However, a combination of etoricoxib (1 mg/kg) with mexidol inhibited locomotor activity in the rotarod test. Nevertheless, it produced no significant effects on the exploratory behavior or anxiety of animals in the open field test and elevated plus maze test.

Recent Trends in Nano-Particulate Carriers for the Diagnosis and Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the presence of aggregated amyloid fibers, neurodegeneration, and loss of memory. Although "Food and Drug Administration" (FDA) approved drugs are available to treat AD, drugs that target AD have limited access to the brain and cause peripheral side effects. These peripheral side effects are the results of exposure of peripheral organs to the drugs. The blood-brain barrier (BBB) is a very sophisticated biological barrier that allows the selective permeation of various molecules or substances. This selective permeation by the BBB is beneficial and protects the brain from unwanted and harmful substances. However, this kind of selective permeation hinders the access of therapeutic molecules to the brain. Thus, a peculiar drug delivery system (nanocarriers) is required. Due to selective permeation of the "blood-brain barrier," nanoparticulate carriers may provide special services to deliver the drug molecules across the BBB. This review article is an attempt to present the role of different nanocarriers in the diagnosis and treatment of Alzheimer's disease. Peer-reviewed and appropriate published articles were collected for the relevant information. Nanoparticles not only traverse the blood-brain barrier but may also play roles in the detection of amyloid β, diagnosis, and drug delivery. Based on published literature, it could be concluded that nano-particulate carriers may traverse the blood-brain barrier via the transcellular pathway, receptor-mediated endocytosis, transcytosis, and may enhance the bioavailability of drugs to the brain. Hence, peripheral side effects could be avoided.