Mild cognitive impairment (MCI) is frequently accompanied by early impairment in gait and postural control. Whether commonly prescribed cognitive therapies differentially influence physical function and neurotrophic signaling remains unclear. We followed 99 older adults with MCI for six months while receiving either the cholinergic agent Donepezil (n = 47, age = 68.3 ± 4.1 years) or the glutamatergic modulator Memantine (n = 52, age = 70.1 ± 3.9 years). Postural balance and gait speed were assessed using the Short Physical Performance Battery. Plasma brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) were measured. Donepezil treatment improved postural balance (Cohen's d = 0.30) and gait speed (d = 0.45), whereas Memantine produced no meaningful changes (d < 0.20 for both outcomes). Repeated-measures ANOVA demonstrated significant Time × Treatment interactions for balance (F(1,97) = 5.9, p < 0.05) and gait speed (F(1,97) = 6.4, p < 0.05). Plasma BDNF increased by approximately 22% (d = 0.46) and GDNF by 19% (d = 0.42) following Donepezil, with no significant biomarker changes in the Memantine group. In the Donepezil group, changes in BDNF correlated with improvements in balance (r2 = 0.13, p = 0.012) and gait speed (r2 = 0.12, p = 0.018), while GDNF changes correlated with balance (r2 = 0.10, p = 0.032) and gait speed (r2 = 0.19, p = 0.002). Multivariate regression analyses demonstrated independent associations of BDNF and GDNF with balance and selected functional outcomes after adjustment for confounders. Donepezil is associated with clinically meaningful improvements in mobility in MCI, accompanied by enhanced neurotrophic support. These findings are consistent with a relationship between cholinergic stimulation, motor function, and neurotrophic pathways in MCI.

Artificial intelligence (AI) and machine learning (ML) are increasingly explored to improve predictive modelling and optimization in pharmaceutical formulation development. This study compared predictive performance of conventional statistical approaches and AI/ML-based models using an experimentally generated dataset from PLGA-mPEG-based Intelligent Nano Depot (iNDEP), smart depot forming long-acting injectable system for sustained co-delivery of Memantine hydrochloride (MH) and Galantamine hydrobromide (GH). Central Composite Design (CCD) dataset of 17 experimental formulations were employed to develop predictive models. The % cumulative drug release (CDR), implant formation time and particle size were measured to determine effects of PLGA-mPEG, Span 80 and Tween 80. Design of Experiments (DoE), SPSS-based Multiple Linear Regression (MLR), Artificial Neural Networks (ANN) and ML workflows in Orange Data Mining and KNIME Analytics Platform were used to produce predictive models. Root mean squared error (RMSE), mean squared error (MSE), and coefficient of determination (R[2]) were used to evaluate model performance. Models developed using DoE were good fit with R[2] values ranging from 0.9882 to 0.9916. The MLR models predicted perfectly (R[2] = 0.866-0.951) for the %CDR responses using SPSS. ANN models successfully captured nonlinear relationships between formulation and response. Analysis of ML workflows indicated varying performance of algorithms depending on response; there was no one model that performed good across all responses. Traditional statistical and AI-based predictive methods complement each other. The integration of DoE with AI- and ML-based modelling offers a comprehensive tool for enhancing prediction accuracy and guiding formulation and optimization of pharmaceutical products.

The management of Alzheimer's disease requires continuous therapeutic intervention due to its progressive nature. Currently, the FDA has approved acetylcholinesterase inhibitors, NMDA receptor antagonists, and disease-modifying monoclonal antibodies for the treatment of Alzheimer's disease. This study aimed to develop a long-acting injectable formulation for symptomatic therapy. An in-situ gel formulation, DM00PG-M13, comprising Lipoid, PLGA (50:50), and sesame oil, was developed and loaded with memantine and donepezil for combination therapy. The optimized gel formulation demonstrated good uniformity with a pH of 7.80 ± 0.015. Rheological and syringeability studies showed a consistent viscosity in the range of 0.20-0.22 Pa·s and an injection force of 9.97 ± 0.29 N using a 22-G needle. In vitro drug release studies performed in phosphate-buffered saline (pH 7.4) demonstrated sustained drug release over one month, with cumulative releases of 82.58% for donepezil and 87.61% for memantine after 30 days. Furthermore, the release kinetics were best described by the Peppas-Sahlin model for donepezil and the Weibull-lag model for memantine. Ex vivo studies evaluating the optimized formulation injected into pig muscle tissue showed release profiles comparable to the in vitro release pattern, with approximately 20% release of donepezil and 26% release of memantine over 7 days, indicating sustained release behavior. Cytotoxicity studies using NIH/3T3 fibroblast cells confirmed the formulation's safety profile. Overall, these results suggest that the drug-loaded DM00PG-M13 formulation can be administered intramuscularly as a depot system for sustained drug release, potentially improving patient compliance.

Catatonia can be difficult to manage when benzodiazepines are poorly tolerated, and electroconvulsive therapy (ECT) cannot be continued. We report the case of a 23-year-old woman with a schizophrenia-spectrum disorder and catatonia presenting with mutism, delayed responses, staring, posturing, waxy flexibility, withdrawal, and abnormal behavior. Treatment with lorazepam was limited by excessive sedation. She then received four bitemporal ECT sessions before she and her mother declined further ECT due to reported adverse effects. Soon after discharge, she was found wandering outside while confused and required readmission. Nine days after her last ECT session, her Bush-Francis Catatonia Rating Scale (BFCRS) severity score was 11. Amantadine 100 mg twice daily was started, and three days later her BFCRS severity score fell to 3, a 72.7% reduction. Because her altered mental status persisted, a neurologic evaluation was performed. Brain MRI, routine electroencephalography (EEG), cerebrospinal fluid (CSF) studies, infectious testing, and neuronal autoantibody testing, including N-methyl-D-aspartate (NMDA) receptor antibody testing, were unremarkable. Amantadine was then increased to 200 mg twice daily, and zolpidem 5 mg nightly was later added. Her final BFCRS severity score was 2. Although delayed ECT effects, concurrent treatment of the underlying psychotic disorder, spontaneous fluctuation, and subsequent interventions preclude causal attribution, this case shows rapid, objectively measured improvement temporally associated with the start of amantadine treatment.

We investigated the effects of angiotensin II receptor blockers (ARBs) on the progression of Alzheimer's disease (AD). This retrospective cohort study used data from the Korean nationwide claims data to identify patients with AD aged 60-79 years in 2010. ARB users and nonusers were 1:1 propensity score matched. Cox proportional hazards regression evaluated AD progression, defined as memantine initiation and mortality. Active-comparator and dose-response analyses were conducted. ARB use was associated with lower risks of memantine initiation (hazard ratio [HR] = 0.79; 95% confidence interval [CI] = 0.70-0.89) and mortality (HR = 0.83; 95% CI = 0.76-0.89). Cumulative exposure analyses showed stronger associations in the highest exposure categories, including 2-3 years of ARB use and ≥ 2 DDD-years, whereas associations in the lower exposure categories were not statistically significant. In active-comparator analyses, ARBs were associated with lower mortality risk than ACE inhibitors and beta-blockers, but not with dihydropyridine calcium channel blockers (CCBs). ARB use may be a reasonable antihypertensive choice in patients with AD, although the comparable outcomes between ARBs and CCBs suggest that these associations may not be unique to ARBs and may instead reflect shared blood pressure-lowering and vascular effects. Further prospective research is warranted to optimize antihypertensive selection in patients with AD.

Antipsychotic-induced parkinsonism (AIP) is a neurologic side effect of first- and second-generation antipsychotics. We present a case of AIP associated with paliperidone with findings concerning for concurrent anticholinergic side effects as a consequence of AIP treatment in a young patient presenting to a community emergency department. Temporarily withdrawing the offending dopamine receptor-blocking antipsychotic medication as well as implementing an adjunct therapy such as benztropine may alleviate the acute presentation of AIP. However, concurrent anticholinergic adverse effects or toxicity may occur because of the antimuscarinic properties of benztropine. In patients in whom anticholinergic toxicity or benztropine-related anticholinergic side effects are a concern, amantadine may be considered as an alternative treatment for AIP. This case report highlights the diagnostic complexity of AIP with suspected benztropine-induced anticholinergic effects, discusses management considerations of this complex presentation, and aims to guide proper treatment in community emergency department settings.

Many neuronal disorders are characterized by glutamate toxicity, which is closely associated with mitochondrial and neuronal dysfunction. The aim of this study was to investigate the link between mitochondrial function and mechanisms of cell death induced by glutamate. The study was carried out on male (C57BL/6) mice and male Sprague Dawley rat acute brain slices (ABSs), as well as male and female organotypic brain slice cultures (BSCs). Mitochondrial respiration, activities of tricarboxylic acid cycle enzymes, and the cell death rate [assessed by lactate dehydrogenase release and histological analyses] were determined. Memantine was used to inhibit excitotoxicity, while ferrostatin-1, rosiglitazone, and deferoxamine were used as inhibitors of the ferroptotic pathway. In astrocytes, pyruvate dehydrogenase complex and oxoglutarate dehydrogenase complex (OGDHC) showed <1% of the enzymatic activity observed in the whole-brain tissue. In BSCs, glutamate exposure induced a marked increase in oxidative phosphorylation-linked mitochondrial respiration, which was independent of OGDHC activity and disappeared when BSC homogenates were analyzed. Glutamate-induced cell death was not alleviated by memantine but was significantly reduced by ferrostatin-1. The activation of ferroptosis by glutamate was also observed in ABSs, as well as the inhibition of lipid peroxidation induced by ferrostatin-1, rosiglitazone, and deferoxamine. Ferrostatin-1 and rosiglitazone additionally inhibited cell death, while deferoxamine did not. The unusual response to deferoxamine requires further elucidation. In summary, our data suggest that elevated glutamate levels enhance neuronal energy metabolism in brain slices, compensating glutamate-mediated Ca[2+] influx and reduce excitotoxicity. In contrast, persistently elevated levels of extracellular glutamate impair the cystine/glutamate antiporter, leading to ferroptosis.

The hepatoprotective potential of amantadine (AMN) against lipopolysaccharide (LPS)-triggered hepatic injury was investigated by evaluating inflammation, inflammasome activation, and apoptosis-related signaling pathways. The study consists of four groups: Control, LPS, LPS + AMN, and AMN. Histopathological changes were evaluated in hematoxylin and eosin-stained liver sections. Immunohistochemical analyses were performed to assess C-reactive protein (CRP), serum amyloid A (SAA), and tumor necrosis factor-alpha (TNF-α). Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were measured as biochemical indicators of liver injury. Interleukin-1 beta (IL-1β), interleukin-18 (IL-18), NLR family pyrin domain containing 3 (NLRP3), thioredoxin-interacting protein (TXNIP), and Bcl-2-associated X protein (BAX) gene expression was determined liver tissue. LPS administration caused severe histopathological damage, inflammatory cell infiltration, and significant elevations in AST and ALT activities. Increased immunoreactivity of CRP, SAA, and TNF-α, together with upregulated IL-1β, IL-18, NLRP3, TXNIP, and BAX expression, indicated enhanced inflammatory and apoptotic responses. Administration of AMN was associated with attenuation of tissue damage, accompanied by lower inflammatory marker levels, decreased serum transaminase activities, and altered expression of key genes related to inflammasome activation and apoptotic pathways. No significant differences were detected between the LPS + AMN groups and controls groups. The present findings are consistent with an association between AMN administration and attenuation of LPS-associated hepatic injury, accompanied by changes in inflammatory responses, inflammasome-related signaling, and apoptosis-related pathways. These findings are consistent with a potential hepatoprotective effect of AMN in inflammation-associated liver injury and warrant further investigation.

Hantavirus fevers (HF) are caused by pathogenic orthohantaviruses and are classified into two clinical forms: hemorrhagic fever with renal syndrome (HFRS), reported in Eurasia, and hantavirus pulmonary syndrome (HPS), reported in the Americas. HF are characterised by an acute course with predominant involvement of internal organs: HFRS is mainly associated with kidney damage, while HPS is characterised by severe lung injury. Both diseases may also affect the central nervous and endocrine systems. In addition, hantavirus fevers are marked by severe complications during the acute phase and a prolonged recovery period. Currently, there is neither a WHO-approved vaccine nor any effective etiotropic anti-hantavirus therapy. The development of antiviral treatment strategies focuses on preventing orthohantavirus entry into cells or suppressing their intracellular replication. One of the main directions in the search for effective anti-hantavirus therapy is the low-molecular-weight compounds development and testing, many of which have demonstrated pronounced antiviral activity against orthohantaviruses through direct or indirect effects on viral RNA polymerase function. The review shows that new antiviral nucleoside compounds development and study has promising potential, as well as their combined use for effective etiotropic, pathogenetic and symptomatic treatment of hantavirus fevers.

L-DOPA remains the most effective therapy for Parkinson's disease (PD), yet its chronic use often induces involuntary movements known as L-DOPA-induced dyskinesia (LID). While abnormal cholinergic interneuron (ChI) activity is a hallmark of both PD and LID, emerging evidence suggests that the temporal organization of acetylcholine (ACh) signaling, rather than its overall magnitude, may determine its functional impact. Under physiological conditions, ChIs exhibit intrinsic delta-frequency activity reflected in coordinated, slow oscillations of extracellular ACh, which are thought to organize striatal network function and movement pattering. To determine how dopamine (DA) depletion and L-DOPA treatment reshape these ACh dynamics, we used in vivo GRAB-ACh fiber photometry in the unilateral 6-OHDA mouse model of parkinsonism. DA depletion disrupted slow ACh rhythmicity, reducing delta-band regularity while increasing higher-frequency phasic activity. Acute L-DOPA broadly suppressed ACh activity across frequencies, partially normalizing this imbalance, but without restoring slow temporal structure. In addition, chronic L-DOPA treatment, associated with established dyskinesia, further impaired delta-band coordination in the DA-depleted striatum during the ON state, while OFF-state activity retained lesion-associated features. The anti-dyskinetic agent amantadine restored low-frequency temporal structure both before and after L-DOPA exposure. Together, these findings reveal a state-dependent reorganization of striatal ACh dynamics, characterized by a shift from coordinated slow oscillations to irregular phasic activity following DA loss, and a further breakdown of slow temporal organization during dyskinetic states. These results highlight the temporal structure of cholinergic signaling as a critical and underappreciated dimension of striatal function in PD and LID.

Cyclodextrin inclusion complexes are widely used in drug delivery systems because they can improve the solubility and stability of drug molecules. However, the stability and transport mechanism of host-guest complexes during transport processes remain poorly understood. In this work, a single α-hemolysin (α-HL) nanopore was employed to investigate the host-guest interactions and dynamic transport behavior of β-cyclodextrin (βCD) and amantadine hydrochloride (Ad) in guanidine hydrochloride (GdnHCl) electrolyte. The results showed that GdnHCl significantly altered the kinetic behavior of βCD and its inclusion complexes within the nanopore. In the conventional KCl electrolyte, βCD-Ad complexes primarily exhibited a sequential transport mode involving dissociation prior to transport. In contrast, in GdnHCl electrolyte, βCD-Ad inclusion complexes entered the nanopore as intact host-guest assemblies and exhibited two transport pathways: in-pore dissociation after entry and translocation without detectable dissociation. The proportion of events involving intact host-guest assemblies increased significantly with increasing GdnHCl concentration, indicating that GdnHCl promotes the transport of inclusion complexes while maintaining host-guest association. Furthermore, a possible higher-order inclusion state was observed in 2.0 M GdnHCl, and the formation process of βCD-Ad complexes was monitored in real time. The fraction of βCD-Ad complexes exhibited a single-exponential growth behavior with an apparent growth rate constant of 0.058 min[-1]. These findings reveal the important role of the electrolyte microenvironment in regulating the stability and transport modes of cyclodextrin host-guest complexes, providing new insights into the transport mechanisms of supramolecular complexes and the design of advanced host-guest delivery systems.