The matrix protein 2 (M2) is one of the most representative and widely studied ion channel proteins, which plays broad biological roles in the life cycle of the influenza A virus. The M2 protein affects the function of host cells and the regulation of cellular homeostasis in an ion channel activity-dependent or-independent manner and it is also the target for anti-influenza virus drugs, such as amantadine and rimantadine. The focus of this review is to summarize the research progress on the M2 protein, such as structure and function, vaccine and drug development as well as antagonist of host innate immune responses. A particular emphasis is placed on the multifaceted roles of M2 beyond canonical ion conduction. Specifically, M2 modulates the MAVS pathway through direct interaction with MAVS and by inducing ROS production, which amplifies interferon-mediated inflammation while paradoxically disrupting autophagic degradation of MAVS aggregation. Concurrently, the M2 protein orchestrates autophagy regulation by inhibiting autophagosome-lysosome fusion and initiating AKT-mTOR signaling, thus stabilizing the viral polymerase to enhance viral replication. A comprehensive understanding of these mechanisms is essential for advancing universal M2-based vaccine strategies and novel host-directed antiviral therapies.

Parkinson's disease (PD) is a common neurodegenerative disorder caused by a spread of misfolded α-synuclein and ascending neuronal degeneration mainly in dopaminergic neurons, leading to progressive nigrostriatal dysfunction and disruption of other pathways. It is clinically defined by its cardinal motor features of bradykinesia, rest tremor and rigidity, which are usually accompanied by a variety of non-motor symptoms. Here we provide a review on recent developments in the pharmacological treatment of PD with a focus on recently approved drugs, new modes of delivery and agents that are in advanced stages of clinical development. Pharmacological dopamine substitution remains the mainstay of symptomatic treatment approaches to control PD motor symptoms. While levodopa is still considered the gold-standard of symptomatic efficacy, its chronic use is associated with the development of response oscillations and drug-induced dyskinesias in a majority of patients. Thus, much effort has been put into developing more continuous ways of levodopa delivery. Novel formulations and modes of application include extended-release (ER) oral levodopa (IPX203), levodopa powder for inhalation, and levodopa infusion therapies through subcutaneous (foslevodopa/foscarbidopa, ND0612) or intrajejunal pumps (levodopa [entacapone] carbidopa intestinal gel). Additionally, different preparations for subcutaneous and sublingual administration of apomorphine, a dopamine agonist with equivalent efficacy to levodopa, are available for the treatment of PD motor fluctuations. Novel dopamine agonists have been developed and tavapadon, a selective dopamine D1/D5 receptor partial agonist, was shown to be efficacious as monotherapy in early PD and adjunct to levodopa in patients with motor fluctuations. In addition, new data on the early use of the COMT-inhibitor opicapone have emerged. This expanding drug armamentarium is complemented by an increasing number of drugs targeting non-dopaminergic pathways with increasing evidence for amantadine's symptomatic efficacy in treating levodopa-induced dyskinesia and motor fluctuations. Beyond the approval of different botulinum toxin preparations for the treatment of sialorrhea, efforts to address the plethora of non-motor symptoms of the disease have not translated to novel PD-specific approvals over the last few years. PD symptoms can usually be satisfactorily controlled in the early to mid-stages, but the progressive course of the disease inevitably leads to increasing functional disability underlining the yet unmet need for disease-modifying therapies. While there is currently no conclusive evidence for disease-modifying efficacy on any of the numerous efforts, we summarize recent late-stage clinical trial evidence focusing on glucagon-like peptide 1 (GLP1) agonists, approaches targeting the glucocerebrosidase (GBA) pathway and inhibition of the leucine-rich repeat kinase 2 (LRRK2), as well as α-synuclein based treatments.

Disorders of consciousness (DoC) are among the most challenging conditions encountered in clinical practice, often complicating both diagnosis and management. Although amantadine has demonstrated benefit in facilitating recovery in patients with traumatic brain injury (TBI)-related DoC, its impact on nontraumatic causes has not been well established. We describe the case of an elderly patient with persistent encephalopathy following an ischemic stroke who experienced marked neurological improvement shortly after initiation of amantadine therapy. This case highlights the potential role of amantadine as a therapeutic option in non-TBI-related disorders of consciousness.

Gambling disorder or pathological gambling is a psychiatric disorder with severe and wide-ranging consequences for the affected individual and their surroundings. While no pharmacological treatment has yet been officially approved for treatment, various drugs have been investigated to date. An electronic literature search was conducted in PubMed to identify open-label trials, randomized controlled trials, meta-analyses, other reviews and case reports. In addition, the ClinicalTrials.gov registry was reviewed to identify recent advancements, investigational drug candidates, and ongoing or forthcoming clinical research related to this topic. In this review we summarize and compare Fluvoxamine, Paroxetine, Sertraline, Citalopram, Bupropion, Nefazodone, Naltrexone, Nalmefene, Naloxone, Lithium, Valproate, Topiramate, Olanzapine, N-acetylcysteine, Disulfiram, Acamprosate, Memantine, Amantadine, Gabapentinoids, Modafinil, GLP-1 receptor agonists and Ketamine/Esketamine. From the above-mentioned substances, many have shown promising results in the treatment of gambling disorder, particularly opioid antagonists. However, the small number of studies on the respective drugs, as well as inconsistent designs and contradictory results, limit the significance and clinical applicability of the findings. Here we discuss the most promising drugs, neurobiological pathomechanisms of gambling disorder and potential methodological designs for future studies on this topic.

The smartphone-based colorimetric approach has emerged as a powerful analytical tool with broad applications, enabling fast and cost-effective measurements, eco-friendly operation with low energy demand, and reasonable analytical performance. In this work, a simple and eco-friendly colorimetric method was developed for the determination of memantine (MEM) in pharmaceutical dosage forms. In this approach, MEM reacts with ascorbic acid to produce a pink-colored product exhibiting two absorption maxima (λ_max) at 386 nm and 530 nm. The color response was captured using a smartphone camera and analyzed digitally with ImageJ software, where the extracted color intensity values were correlated with MEM concentration. A conventional spectrophotometric method relying on the absorbance at 386 nm was also established. Both methods exhibited excellent linearity over the concentration range of 5.0-50.0 µg/mL. The smartphone-based method showed a limit of detection (LOD) of 0.45 µg/mL and limit of quantitation (LOQ) of 1.36 µg/mL, while the spectrophotometric method exhibited a LOD of 0.0615 µg/mL and LOQ of 0.19 µg/mL. The greenness of the methods was evaluated using the newly introduced EPPI tool, a comprehensive metric that assesses greenness, applicability, and analytical performance. The results are presented as pie charts and numerical scores. The total scores for the smartphone and colorimetric approaches were 84.4 and 82.4, respectively, indicating the superiority of the smartphone-based method in terms of sustainability and practical applicability.

Despite recent advances in neuropsychiatry, translational development for many targets remains challenging, particularly when receptors exist as families with complex subunit-dependent pharmacology and safety concerns. This is the case for NMDA receptor (NMDAR) antagonists. R,S-ketamine illustrates this issue: although it produces rapid antidepressant effects in the clinic, its use is limited by dissociative side effects and potential long-term cognitive impairment. Preclinical studies have also linked it to neuropathological alterations such as Olney's lesions. These limitations highlight the need for deeper mechanistic characterization beyond simple receptor inhibition. Recently, we investigated RST-01, a novel fluoroalkyl derivative of amantadine, as a potential treatment for early post-traumatic stress disorder (PTSD). In preclinical rat models, RST-01 showed efficacy without observable dissociation and without inducing Olney's lesions, an established marker of neurotoxicity unlike R,S-ketamine and memantine reported in the literature. To better understand these safety differences, we examined the target-engagement profiles of RST-01, ketamine, and memantine in preclinical systems. Specifically, we assessed their selectivity across NMDAR subtypes. Using in-vitro electrophysiological assays, we determined IC50 values for human GluN1/GluN2A-D receptors and applied a multidimensional analytical approach to compare their subunit selectivity patterns. Our results revealed distinct pharmacological signatures across the four GluN2 subunits. When represented in multidimensional space, RST-01 displayed a more differentiated selectivity profile than ketamine or memantine. This subunit-specific characterization provides a mechanistic framework to interpret differences in adverse-effect profiles and safety margins observed in preclinical models, supporting the development of safer and more selective NMDAR-targeting therapies.

This article investigates the progression of sleep disturbances in Alzheimer's disease (AD) and the mechanisms by which these disturbances may accelerate neurodegeneration. Key electrophysiological patterns identified through polysomnography in patients with AD and sleep disorders are analyzed. Therapeutic interventions are reviewed, with non-pharmacological and pharmacological approaches considered separately. The roles of cognitive behavioural therapy, relaxation techniques, and optimization of sleep conditions are emphasized. Current pharmacological treatment options are discussed, highlighting the need for careful drug selection due to the high risk of adverse effects and the potential dangers of certain medications, such as benzodiazepines and cyclopyrroles, in elderly patients with cognitive impairment. The use of memantine as a foundational therapy is given particular attention, as it may improve both cognitive function and sleep quality.

Cognitive impairments are important therapeutic targets in epilepsy medication; however, effective pharmacological treatments for epilepsy patients with comorbid cognitive impairment have not been established. Effects of chronic administration of MK-801 (noncompetitive NMDA receptor inhibitor), memantine (low-affinity extrasynaptic-NMDA receptor preferential inhibitor), FP802 (TwinF interface inhibitor), and probenecid (pannexin1 containing hemichannel inhibitor) for 14 days on epileptic seizure frequency, sucrose preference, extracellular levels of L-glutamate and D-serine, expression of GluN2A and GluN2B, and phosphorylated CREB levels in the frontal cortex (epileptic focus region) were investigated using a genetic rat model of epilepsy with cognitive impairment (S286L-TG rats). Seizure frequency of S286L-TG was reduced by chronic administration of probenecid, MK-801, and memantine + FP802, but not by memantine or FP802 alone. Decreased sucrose preference of S286L-TG relative to wild-type littermate rats was restored by memantine and memantine + FP802, but aggravated by MK-801 without being affected by probenecid or FP802. Downregulated GluN2A/GluN2B expression in S286L-TG relative to wild-type was restored by probenecid, memantine, and memantine + FP802, but further decreased by MK-801, and was unaffected by FP802. Upregulated basal extracellular L-glutamate/D-serine levels in S286L-TG were restored by probenecid and memantine + FP802, further increased by MK-801, and unaffected by FP802. In contrast, chronic memantine alone restored the basal D-serine increasing but did not affect basal L-glutamate. These results suggest the possibility that a combination of suppressing TRPM4/NMDA receptor complex and extrasynaptic NMDA receptor may contribute to reducing epileptic seizures and ameliorating dysfunction/bias of preference regulation, providing a potential therapeutic strategy for epilepsy patients comorbid with cognitive impairments.