Edaravone: A new drug approved for ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive, adult onset neurodegenerative disease that is always fatal. The history of ALS drug discovery is fraught with many stops and starts. It took 22 years after the FDA approval of the anti-excitotoxic drug Riluzole before another drug was found to be effective in altering ALS progression: the anti-oxidant Edaravone.

Modeling disrupted synapse formation in wolfram syndrome using hESCs-derived neural cells and cerebral organoids identifies Riluzole as a therapeutic molecule.

Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders, which are also manifested by wolfram syndrome (WS). Whether and how the causative gene WFS1 deficiency affects synapse formation remain elusive. By mirroring human brain development with cerebral organoids, WFS1-deficient cerebral organoids not only recapitulate the neuronal loss in WS patients, but also exhibit significantly impaired synapse formation and function associated with reduced astrocytes. WFS1 deficiency in neurons autonomously delays neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impairs neurite outgrowth and synapse formation with elevated cytosolic calcium. Intriguingly, WFS1 deficiency in astrocytes decreases the expression of glutamate transporter EAAT2 by NF-κB activation and induces excessive glutamate. When co-cultured with wildtype neurons, WFS1-deficient astrocytes lead to impaired neurite outgrowth and increased cytosolic calcium in neurons. Importantly, disrupted synapse formation and function in WFS1-deficient cerebral organoids and impaired neurite outgrowth affected by WFS1-deficient astrocytes are efficiently reversed with Riluzole treatment, by restoring EAAT2 expression in astrocytes. Furthermore, Riluzole rescues the depressive-like behavior in the forced swimming test and the impaired recognition and spatial memory in the novel object test and water maze test in Wfs1 conditional knockout mice. Altogether, our study provides novel insights into how WFS1 deficiency affects synapse formation and function, and offers a strategy to treat this disease.

Emerging drugs for the treatment of irritability associated with autism spectrum disorder.

INTRODUCTION: Autism spectrum disorder (ASD) is an early-onset disorder with a prevalence of 1% among children and reported disability-adjusted life years of 4.31 million. Irritability is a challenging behavior associated with ASD, for which medication development has lagged. More specifically, pharmacotherapy effectiveness may be limited against high adverse effects (considering side effect profiles and patient medication sensitivity); thus, the possible benefits of pharmacological interventions must be balanced against potential adverse events in each patient. AREAS COVERED: After reviewing the neuropathophysiology of ASD-associated irritability, the benefits and tolerability of emerging medications in its treatment based on randomized controlled trials were detailed in light of mechanisms and targets of action. EXPERT OPINION: Succeeding risperidone and aripiprazole, monotherapy with memantine may be beneficial. In addition, N-acetylcysteine, galantamine, sulforaphane, celecoxib, palmitoylethanolamide, pentoxifylline, simvastatin, minocycline, amantadine, pregnenolone, prednisolone, riluzole, propentofylline, pioglitazone, and topiramate, all adjunct to risperidone, and clonidine and methylphenidate outperformed placebo. These effects were through glutamatergic, γ-aminobutyric acidergic, inflammatory, oxidative, cholinergic, dopaminergic, and serotonergic systems. All medications were reported to be safe and tolerable. Considering sample size, follow-up, and effect size, further studies are necessary. Along with drug development, repositioning and combining existing drugs supported by the mechanism of action is recommended.

Functional Polyphenol-Based Nanoparticles Boosted the Neuroprotective Effect of Riluzole for Acute Spinal Cord Injury.

Riluzole is commonly used as a neuroprotective agent for treating traumatic spinal cord injury (SCI), which works by blocking the influx of sodium and calcium ions and reducing glutamate activity. However, its clinical application is limited because of its poor solubility, short half-life, potential organ toxicity, and insufficient bioabilities toward upregulated inflammation and oxidative stress levels. To address this issue, epigallocatechin gallate (EGCG), a natural polyphenol, was employed to fabricate nanoparticles (NPs) with riluzole to enhance the neuroprotective effects. The resulting NPs demonstrated good biocompatibility, excellent antioxidative properties, and promising regulation effects from the M1 to M2 macrophages. Furthermore, an in vivo SCI model was successfully established, and NPs could be obviously aggregated at the SCI site. More interestingly, excellent neuroprotective properties of NPs through regulating the levels of oxidative stress, inflammation, and ion channels could be fully demonstrated in vivo by RNA sequencing and sophisticated biochemistry evaluations. Together, the work provided new opportunities toward the design and fabrication of robust and multifunctional NPs for oxidative stress and inflammation-related diseases via biological integration of natural polyphenols and small-molecule drugs.

Electrochemical detection of the neurotransmitter glutamate and the effect of the psychotropic drug riluzole on its oxidation response.

Glutamate is the main excitatory neurotransmitter in the brain and plays a leading role in degenerative diseases, such as motor neuron diseases. Riluzole is a glutamate regulator and a therapeutic drug for motor neuron diseases. In this work, the interaction between glutamate and riluzole was studied using cyclic voltammetry and square-wave voltammetry at a glassy carbon electrode (GCE). It was shown that glutamate underwent a two-electron transfer reaction on the GCE surface, and the electrochemical detection limits of glutamate and riluzole were 483 µmol/L and 11.47 µmol/L, respectively. The results confirm that riluzole can promote the redox reaction of glutamate. This work highlights the significance of electrochemical technology in the sensing detection of the interaction between glutamate and related psychotropic drugs.

Adherence to riluzole therapy in patients with amyotrophic lateral sclerosis in three Italian regions-The CAESAR study.

PURPOSE: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease. Riluzole may increase survival and delay the need for mechanical ventilation. The CAESAR project ('Comparative evaluation of the efficacy and safety of drugs used in rare neuromuscular and neurodegenerative diseases', FV AIFA project 2012-2013-2014) involves evaluating prescribing patterns, and analysing effectiveness and comparative safety of drugs, in patients with neurodegenerative diseases. The aim of this study is to evaluate adherence to riluzole in patients with ALS during the first year of use, identifying adherence clusters. METHODS: A retrospective cohort study was conducted using administrative data from Latium, Tuscany, and Umbria. We identified subjects with a new diagnosis of ALS between 2014 and 2019, with the first dispensation of riluzole within 180 days of diagnosis. We considered a two-year look-back period for the characterization of patients, and we followed them from the date of first dispensing of riluzole for 1 year. We calculated 12 monthly adherence measures, through a modified version of the Medication Possession Ratio, estimating drug coverage with Defined Daily Dose. Adherence trajectories were identified using a three-step method: (1) calculation of statistical measures; (2) principal component analysis; (3) cluster analysis. Patient characteristics at baseline and during follow-up were described and compared between adherence groups identified. RESULTS: We included 264 ALS patients as new users of riluzole in Latium, 344 in Tuscany, and 63 in Umbria. We observed a higher frequency of males (56.2%) and a mean age of 67.4 (standard deviation, SD, 10.4) in the overall population. We identified two clusters in all regions: one more numerous, including adherent patients (60%, 74%, 88%, respectively), and another one including patients who discontinued therapy (40%, 26%, 12%, respectively). In Tuscany patients discontinuing riluzole more frequently died (28.6% vs. 15.4%, p-value <0.01). Additionally, low-adherers had a higher frequency of central nervous system disorders (69.0% vs. 52.5%, p-value 0.01), and a greater use of non-pharmacological treatments (p-values ≤0.01 for invasive ventilation and tracheostomy). We did not observe any differences in Lazio, whereas in Umbria we observed a higher use of drugs for dementia-related psychiatric problems among low-adherers (57.1% vs. 7.8%, respectively, p-value <0.01), although with small numbers. CONCLUSION: Most ALS patients who start riluzole adhere to therapy during the first year. Patients who discontinue therapy early show greater fragility and mortality.

Using an expanded algorithm to estimate prevalence of amyotrophic lateral sclerosis in U.S. and UK.

BACKGROUND: There is an increasing need to better understand the burden of amyotrophic lateral sclerosis (ALS) using real-world data (RWD). However, identifying ALS cases using RWD presents several challenges due to the rarity of ALS and the differences in database coding systems. METHODS: MarketScan claims, and the UK Clinical Practice Research Datalink (CPRD) databases were searched for diagnosis codes of ALS or MND, the only drugs approved for treating ALS (riluzole and edaravone) and clinical visits with 12-month enrolment prior to 1 January 2011. The main algorithm required ≥ 1 ALS diagnosis code together with prescriptions or clinical visits. We expanded the existing algorithm to identify unspecific (possible) ALS group that had codes for motor neuron disease (MND) and the ALS drugs. The study period was from 1 January 2011 until 31 December 2020. RESULTS: We identified 16,246 patients with ≥ 1 ALS code in Marketscan (denominator n = 85,279,619), yet only 184 were found in the UK CPRD (denominator n = 21,318,589). Using the main algorithm 9,433 ALS patients were included in MarketScan, with a prevalence ranged between 4.5 per 100,000 in 2019 and 6.2 in 2015. In MarketScan, 3,658 (4.3 per 100,000) had ≥ 1 MND code and the ALS drug codes (possible cases). In CPRD, 47.9% of 2,785 patients with ≥ 1 MND code had a prescription for riluzole (6.3 per 100,000), regarded as possible ALS cases. CONCLUSIONS: The expanded algorithm enabled the identification of a large population with ALS, or possible ALS, and the estimation of ALS prevalence in MarketScan and CPRD.

An updated systematic review of neuroprotective agents in the treatment of spinal cord injury.

This systematic review aims to summarize the findings from all clinical randomized trials assessing the efficacy of potential neuroprotective agents in influencing the outcomes of acute spinal cord injuries (SCI). Following the PRISMA guidelines, we conducted comprehensive searches in four electronic databases (PubMed, Scopus, Cochrane Library, and Web of Science) up to September 5th, 2023. Our analysis included a total of 30 studies. We examined the effects of 15 substances/drugs: methylprednisolone, tirilazad mesylate, erythropoietin, nimodipine, naloxone, Sygen, Rho protein antagonist, granulocyte colony-stimulating factor, autologous macrophages, autologous bone marrow cells, vitamin D, progesterone, riluzole, minocycline, and blood alcohol concentration. Notable improvements in neurological outcomes were observed with progesterone plus vitamin D and granulocyte colony-stimulating factor. In contrast, results for methylprednisolone, erythropoietin, Sygen, Rho Protein, and Riluzole were inconclusive, primarily due to insufficient sample size or outdated evidence. No significant differences were found in the remaining evaluated drugs. Progesterone plus vitamin D, granulocyte colony-stimulating factor, methylprednisolone, Sygen, Rho Protein, and Riluzole may enhance neurological outcomes in acute SCI cases. It is worth noting that different endpoints or additional subgroup analyses may potentially alter the conclusions of individual trials. Therefore, certain SCI grades may benefit more from these treatments than others, while the overall results may remain inconclusive.

Do long-lasting effects of epidural polarization of afferent fibres depend on persistent sodium current?

Few attempts have so far been made to define the mechanisms underlying the hour-long effects of trans-spinal stimulation combined with epidural polarization. In the present study, we investigated the potential involvement of non-inactivating sodium channels in afferent fibres. To this end, riluzole, a blocker of these channels, was administered locally to the dorsal columns close to the site of the excitation of afferent nerve fibres by epidural stimulation in deeply anaesthetized rats in vivo. Riluzole did not prevent the induction of the polarization-evoked sustained increase in the excitability of dorsal column fibres but tended to weaken it. It likewise weakened but did not abolish the sustained polarization-evoked shortening of the refractory period of these fibres. These results lead to the conclusion that the persistent sodium current may contribute to the sustained post-polarization-evoked effects but is only partly involved in both the induction and the expression of these effects.

Treatment with the copper compound CuATSM has no significant effect on motor neuronal pathology in patients with ALS.

AIMS: Although the orally available brain-penetrant copper compound CuATSM has demonstrated promising effects in SOD1-linked mouse models, the impact of CuATSM on disease pathology in patients with amyotrophic lateral sclerosis (ALS) remains unknown. METHODS: The present study set out to address this deficit by performing the first pilot comparative analysis of ALS pathology in patients that had been administered CuATSM and riluzole [N = 6 cases composed of ALS-TDP (n = 5) and ALS-SOD1 (n = 1)] versus riluzole only [N = 6 cases composed of ALS-TDP (n = 4) and ALS-SOD1 (n = 2)]. RESULTS: Our results revealed no significant difference in neuron density or TDP-43 burden in the motor cortex and spinal cord of patients that had received CuATSM compared with patients that had not. In patients that had received CuATSM, p62-immunoreactive astrocytes were observed in the motor cortex and reduced Iba1 density was found in the spinal cord. However, no significant difference in measures of astrocytic activity and SOD1 immunoreactivity was found with CuATSM treatment. DISCUSSION: These findings, in this first postmortem investigation of patients with ALS in CuATSM trials, demonstrate that in contrast to that seen in preclinical models of disease, CuATSM does not significantly alleviate neuronal pathology or astrogliosis in patients with ALS.

Amyotrophic Lateral Sclerosis in Southwestern and Eastern Finland.

INTRODUCTION: The incidence of amyotrophic lateral sclerosis (ALS) worldwide is approximately 1-2.6/1,000,000 and prevalence is 5-6/100,000. ALS has been suggested to be relatively common in Finland, but epidemiological information on the subject is scarce and outdated. MATERIAL AND METHODS: Patients with ALS diagnostic codes were identified from mandatory administrative registries in the provinces of Southwestern Finland (population circa 430,000) and North Karelia (population circa 170,000), together comprising 11.7% of the total population of Finland. The diagnoses were verified, and data were extracted by reviewing the patient records. Incidence period was 2010-2018, and the prevalence date was December 31, 2018. Age-standardization was performed using the European Standard Population 2013 (ESP2013). RESULTS: Overall crude incidence of ALS was 4.2/100,000 person-years in Southwestern Finland (ESP2013: 4.0/100,000) and 5.6/100,000 person-years in North Karelia (ESP2013: 4.8/100,000), while crude prevalences were 11.9/100,000 (ESP2013: 10.5/100,000) and 10.9/100,000 (ESP2013: 9.3/100,000), respectively. Mean age at diagnosis was 65.5-71.6 years in women (higher in Southwestern Finland compared to North Karelia, p = 0.003) and 64.7-67.3 years in men (no difference between provinces, p = 0.39). The diagnosis had been made in 50% before the age of 70 years in Southwestern Finland and before the age of 65 years in 51% in North Karelia. Genetic testing had been conducted in 28% of all patients with the most common findings being SOD1 and C9orf72. After the diagnosis, mean survival was 2.0-2.7 and median survival 1.3-1.4 years. Onset phenotype (p < 0.001), age at diagnosis (p < 0.001), and genotype (p = 0.001) predicted survival. Riluzole had been used by 25% of patients and tracheostomy and invasive ventilation (TIV) had been performed in <1%. CONCLUSIONS: Both incidence and prevalence of ALS in Finland are among the highest in the world but with some notable differences between the eastern and southwestern parts of the country. Low median life expectancy may be related to the advanced age of patients and the high prevalence of C9orf72 repeat expansion in Finland as well infrequent use of TIV and riluzole.

Synthesis, characterization, in-silico, and pharmacological evaluation of new 2-amino-6­trifluoromethoxy benzothiazole derivatives.

Alzheimer's disease (AD), a relentless neurodegenerative disorder, is still waiting for safer profile drugs, risk factors affecting AD's pathogenesis include aß accumulation, tau protein hyperphosphorylation, and neuroinflammation. This research aimed to synthesize 2-amino-6­trifluoromethoxy benzothiazole schiff bases. Synthesis was straightforward, combining the riluzole skeleton with compounds containing the azomethine group. Schiff bases synthesized were characterized spectroscopically using proton NMR (1H NMR), and FTIR. In-vivo biological evaluation against scopolamine-induced neuronal damage revealed that these newly synthesized schiff bases were effective in protecting neurons against neuroinflammatory mediators. In-vitro results revealed that these compounds had remarkable potential in improving the anti-oxidant levels. It downregulated glutathione (GSH), glutathione S-transferase (GST), catalase levels, and upregulated lipid peroxidation (LPO) levels. Immunohistochemical studies revealed that groups treated with the newly synthesized schiff bases had reduced expression of inflammatory mediators such as cyclooxygenase 2 (COX-2), JNK, tumor necrosis factor (TNF-α), nuclear factor kappa B (NF-kB) in contrast to the disease group. Moreover, molecular docking studies on these compounds also showed that they possessed a better binding affinity for above mentioned inflammatory mediators. The results of these studies showed that 2-amino-6-trifluoromethoxy benzothiazole schiff bases are remarkably effective against oxidative stress-mediated neuroinflammation.

Biological aspects of nitrogen heterocycles for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rare, cumulative neurological deteriorating disease that disturbs the neurons (nerve cells) that control voluntary muscle movement (those muscles we choose to move). Currently, the Food and Drug Administration (FDA) approved drugs such as Radicava, Rilutek, Tiglutik, Exservan, and Nuedexta to treat ALS. Given the wide range of pharmaceutical applications of heterocyclic compounds, especially those containing the nitrogen ring systems such as pyridine, pyrimidine, and indole. These molecular frameworks have piqued the interest of medicinal chemists for further investigation in a variety of diseases. We have found several review works done on this research topic. Until now, no reviews published on the nitrogen heterocycles for treating ALS. This review examines the major causes of ALS, a brief history of medications that have been used to treat it so far, and the most recent breakthroughs in nitrogen ring systems for treating ALS. The novelty of this study provides insights on several effective synthetic techniques for nitrogen-based heterocyclic medications that operate as potent anti-inflammatory treatments and guard against ALS. KEY POINTS: • Pharmacological activity of heterocyclic compounds. • Neurodegenerative diseases and their drawbacks are discussed in detail. • Recent survey of nitrogen heterocycles in treating ALS disease are highlighted.

Riluzole-Loaded Nanostructured Lipid Carriers for Hyperproliferative Skin Diseases.

Nanocarriers, and especially nanostructured lipid carriers (NLC), represent one of the most effective systems for topical drug administration. NLCs are biodegradable, biocompatible and provide a prolonged drug release. The glutamate release inhibitor Riluzole (RLZ) is a drug currently used for amyotrophic lateral sclerosis (ALS), with anti-proliferative effects potentially beneficial for diseases with excessive cell turnover. However, RLZ possesses low water solubility and high light-sensibility. We present here optimized NLCs loaded with RLZ (RLZ-NLCs) as a potential topical treatment. RLZ-NLCs were prepared by the hot-pressure homogenization method using active essential oils as liquid lipids, and optimized using the design of experiments approach. RLZ-NLCs were developed obtaining optimal properties for dermal application (mean size below 200 nm, negative surface charge and high RLZ entrapment efficacy). In vitro release study demonstrates that RLZ-NLCs allow the successful delivery of RLZ in a sustained manner. Moreover, RLZ-NLCs are not angiogenic and are able to inhibit keratinocyte cell proliferation. Hence, a NLCs delivery system loading RLZ in combination with natural essential oils constitutes a promising strategy against keratinocyte hyperproliferative conditions.

New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments.

Currently, there are no effective drugs for the treatment of amyotrophic lateral sclerosis (ALS). Only two drugs-edaravone and riluzole-have been approved, but they have very limited efficacy. The aim of this work was to modify the structural core of the Edaravone-phenylpyrazolone moiety and combine it with aminoadamantane pharmacophore in order to expand the spectrum of its action to a number of processes involved in the pathogenesis of ALS. New conjugates of edaravone derivatives with 1-aminoadamantanes combined with alkylene or hydroxypropylene spacers were synthesized, and their biological activity was investigated. Compounds were found that could inhibit lipid peroxidation and calcium-related mitochondrial permeability, block fast sodium currents of CNS neurons, and reduce aggregation of the mutated form of the FUS-protein typical to ALS. So, the proposed modification of the edaravone molecule has allowed the obtaining of new original structures that combine some prospective therapeutic mechanisms against key chains of the pathogenesis of ALS. The identified lead compounds can be used for further optimization and development of new promising drugs on this basis for the treatment of ALS.

Treatment of hereditary amyotrophic lateral sclerosis.

Currently, only four molecules can be prescribed for amyotrophic lateral sclerosis (ALS), of which only one is approved worldwide for this indication, riluzole. Although progress in the therapeutic field remains unsatisfactory, we have to notice that genetics have undergone impressive improvements over the last three decades and, by extension, our knowledge of ALS cases linked to a pathogenic mutation that accounts for 10% of all cases (either sporadic or familiar) and is currently called hereditary ALS (hALS). In many neurological diseases treatment targeting pathogenic genes have significatively improved the natural profile of the disease: this is perfectly illustrated for familial amyloid neuropathy and spinal muscular atrophy. Because of these findings and the urgent need to find a cure for ALS, many trials have focused on familial ALS targeting the four most important genes linked to the disease: C9orf72, SOD1, TARDBP and FUS. We propose in this review an update on the perspectives of treatment that may be available in mid-term in hALS and will discuss in the last part the potential consequences for asymptomatic relatives of patients with a hALS and for ALS patients.

Management of amyotrophic lateral sclerosis in clinical practice: Results of the expert consensus using the Delphi methodology.

Amyotrophic lateral sclerosis (ALS) is a rare disease characterized by a progressive and irreversible degeneration of upper and lower motor neurons leading to death. In France, limited data exist describing the criteria used in clinical practice for diagnosis and follow-up, and how novel therapies may fit in. The objective of this Delphi panel was to obtain an overview of current French practices in ALS diagnosis, management, and follow-up by determining the scales and criteria used in clinical practice outside of clinical trials, as well as the place of a future treatment like AMX0035, acting on endoplasmic reticulum (ER) stress and mitochondrial dysfunction, in the current therapeutic strategies. A questionnaire was administered to 24 ALS healthcare providers practicing in ALS centers in France. Two rounds of remote voting were organized, before proposition of final consensus statements. Consensus was considered reached when at least 66% of the voters agreed. Consensus were obtained to define the new Gold Coast criteria as the ones used in clinical practice to establish the diagnosis of ALS, thus replacing the revised El Escorial criteria, considered too complex and now mainly used to characterize the patient populations to be included in clinical trials. The clinical factors considered to establish ALS diagnosis are mainly the demonstration of progression of the motor deficit and elimination of differential diagnoses. The ALSFRS-R scale is used in daily clinical practice to assess patient's functional impairment in terms of number of points lost, with the bulbar, respiratory, and fine motor subscores being the most important to evaluate independently. A critical medical need was identified regarding the provision of new therapeutic alternatives in ALS. The panel members would support the earliest management of patients. In this landscape, based on data from a very encouraging phase II (Centaur trial), AMX0035 represents a new tool of choice in current treatment strategies for all patients for whom experts are confident in the diagnosis of ALS, in combination with riluzole. These results will need to be confirmed by the ongoing phase III trial (Phoenix trial).

Development and Evaluation of Amorphous Solid Dispersion of Riluzole with PBPK Model to Simulate the Pharmacokinetic Profile.

In the current work, screening of polymers viz. polyacrylic acid (PAA), polyvinyl pyrrolidone vinyl acetate (PVP VA), and hydroxypropyl methyl cellulose acetate succinate (HPMC AS) based on drug-polymer interaction and wetting property was done for the production of a stable amorphous solid dispersion (ASD) of a poorly water-soluble drug Riluzole (RLZ). PAA showed maximum interaction and wetting property hence, was selected for further studies. Solid state characterization studies confirmed the formation of ASD with PAA. Saturation solubility, dissolution profile, and in vivo pharmacokinetic data of the ASD formulation were generated in rats against its marketed tablet Rilutor. The RLZ:PAA ASD showed exponential enhancement in the dissolution of RLZ. Predicted and observed pharmacokinetic data in rats showed enhanced area under curve (AUC) and Cmax in plasma and brain with respect to Rilutor. Furthermore, a physiologically based pharmacokinetic (PBPK) model of rats for Rilutor and RLZ ASD was developed and then extrapolated to humans where physiological parameters were changed along with a biochemical parameter. The partition coefficient was kept similar in both species. The model was used to predict different exposure scenarios, and the simulated data was compared with observed data points. The PBPK model simulated Cmax and AUC was within two times the experimental data for plasma and brain. The Cmax and AUC in the brain increased with ASD compared to Rilutor for humans showing its potential in improving its biopharmaceutical performance and hence enhanced therapeutic efficacy. The model can predict the RLZ concentration in multiple compartments including plasma and liver.

Live-Cell Synchrotron-Based FTIR Evaluation of Metabolic Compounds in Brain Glioblastoma Cell Lines after Riluzole Treatment.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor, characterized by short median survival and an almost 100% tumor-related mortality. The standard of care treatment for newly diagnosed GBM includes surgical resection followed by concomitant radiochemotherapy. The prevention of disease progression fails due to the poor therapeutic effect caused by the great molecular heterogeneity of this tumor. Previously, we exploited synchrotron radiation-based soft X-ray tomography and hard X-ray fluorescence for elemental microimaging of the shock-frozen GBM cells. The present study focuses instead on the biochemical profiling of live GBM cells and provides new insight into tumor heterogenicity. We studied bio-macromolecular changes by exploring the live-cell synchrotron-based Fourier transform infrared (SR-FTIR) microspectroscopy in a set of three GBM cell lines, including the patient-derived glioblastoma cell line, before and after riluzole treatment, a medicament with potential anticancer properties. SR-FTIR microspectroscopy shows that GBM live cells of different origins recruit different organic compounds. The riluzole treatment of all GBM cell lines mainly affected carbohydrate metabolism and the DNA structure. Lipid structures and protein secondary conformation are affected as well by the riluzole treatment: cellular proteins assumed cross ß-sheet conformation while parallel ß-sheet conformation was less represented for all GBM cells. Moreover, we hope that a new live-cell approach for GBM simultaneous treatment and examination can be devised to target cancer cells more specifically, i.e., future therapies can develop more specific treatments according to the specific bio-macromolecular signature of each tumor type.

Riluzole restores memory and brain energy metabolism in AßPP-PS1 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder leading to memory loss and impaired cognition. Despite several decades of research, AD therapeutic is not available. In this study, we have investigated the impact of a chronic intervention of riluzole on memory and neurometabolism in the AßPP-PS1 mouse model of AD. The 10-month-old AßPP-PS1 mice were administered 30 doses of riluzole (6 mg/kg, intragastrically) on an alternate day for two months. The memory was assessed using Morris Water Maze, while neurometabolism was evaluated by 1H-[13C]-NMR spectroscopy together with an intravenous infusion of [1,6-13C2]glucose. The normal saline-treated AßPP-PS1 mice exhibited a decrease in learning and memory that were restored to the control level following riluzole treatment. Most interestingly, the reduced 13C labeling of GluC4 and AspC3 from [1,6-13C]glucose in the AßPP-PS1 mice was restored to the control level following riluzole intervention. As a consequence, chronic riluzole treatment improved metabolic activity of glutamatergic neurons in AßPP-PS1 mice. Together these data suggest that riluzole may be useful for improving cognition in AD.