Rats were randomly assigned to sham surgery, myocardial infarction with saline, or myocardial infarction followed by combined drug treatment, with nine animals in each group. Rats in the combination group received bevantolol at 10.5 mg/kg and tandospirone at 3.15 mg/kg by intragastric administration for seven days. Infarcted controls received 5 mL/kg of physiological saline. The doses were converted from human doses through a body-surface-area method, and tissues were collected after the final administration.

Investigators assessed infarct size using TTC/Evans blue staining. In this method, tissue unstained by Evans blue represented the ischemic area, while tissue not stained by TTC within that area represented infarction. Quantitative histological analyses used three biological replicates per group. Hematoxylin and eosin staining showed disorganized myocardium, inflammatory-cell infiltration, collagenous fibers, and visible scar in infarcted control rats. These abnormalities were less pronounced in rats receiving the combination, supporting the observation that combined treatment mitigated myocardial pathological damage after infarction.

Masson staining was used to quantify fibrosis through the collagen volume fraction, defined as the proportion of positively stained collagen area relative to total tissue area. Collagen volume fraction was higher after infarction than in sham-operated rats and lower with combined treatment than in saline-treated infarcted controls. TUNEL staining, which detects DNA fragmentation rather than apoptosis specifically, also showed a higher proportion of positive cells after infarction and a lower proportion following combined treatment. The investigators cautioned that TUNEL-positive cells can reflect multiple programmed cell-death pathways, including pyroptosis, so the assay did not quantify the separate contributions of apoptosis and pyroptosis to cardiomyocyte loss.

Enzyme-linked immunosorbent assays used six biological replicates per group to measure serum creatine kinase-MB and cardiac troponin I, serum and myocardial-tissue concentrations of interleukin-1β and interleukin-18, and myocardial-tissue concentrations of interleukin-1β and interleukin-18. Compared with sham-operated animals, infarcted controls had higher concentrations of the myocardial injury markers and inflammatory cytokines. The combined-treatment group had lower concentrations of all six measured analyte-location combinations than infarcted controls. Quantitative reverse-transcription polymerase chain reaction and Western blotting likewise showed higher myocardial interleukin-1β and interleukin-18 messenger RNA and protein expression after infarction and lower expression with the combination.

The investigators next examined NLRP3, cleaved Caspase-1, and the N-terminal domain of gasdermin D, designated GSDMD-N. Immunohistochemical staining, qRT-PCR, and Western blotting showed increased expression of these markers in infarcted controls relative to sham-operated rats and decreased expression in the combination group. These findings demonstrate lower molecular-marker expression following combined treatment; they do not, by themselves, prove that the treatment directly inhibited the pathway or that pathway suppression mediated the histological effects.

The study also assessed the precursor proteins pro-Caspase-1 and full-length GSDMD. Both were elevated after myocardial infarction. Their abundance was numerically lower in the combination group, but the differences from infarcted controls were not significant. By contrast, the ratios of cleaved Caspase-1 to pro-Caspase-1 and GSDMD-N to full-length GSDMD increased after infarction and were significantly reduced by combined treatment. The authors interpreted this pattern as consistent with less cleavage and activation of Caspase-1 and GSDMD rather than a major change in precursor-protein abundance.

Several limitations constrain the findings. The experiment did not include myocardial-infarction groups treated with bevantolol or tandospirone alone, so it cannot show that the combination was more effective than either drug or that the agents interacted synergistically. It also did not measure cardiac function, survival, or outcomes beyond the one-week treatment period, and it did not test post-infarction anxiety-like or depression-like behavior. Alternative stress-modulating drugs were not evaluated. The mechanistic interpretation remains bounded by the absence of a validated NLRP3-specific inhibitor or activator and definitive functional pyroptosis assays.

Cell-type-specific co-staining was also not performed, so the experiment could not identify which myocardial or inflammatory cell populations generated the pathway signals. These results therefore support an association between combined bevantolol and tandospirone treatment, reduced myocardial injury markers, and lower NLRP3/Caspase-1/GSDMD-associated marker expression in a short-term male rat infarction model. They do not demonstrate human clinical efficacy, long-term functional benefit, or a causal pathway mechanism.

Subject of Research: Short-term rat myocardial infarction study of bevantolol plus tandospirone and NLRP3/Caspase-1/GSDMD-associated markers

Article Title: Protection of beta-blocker and 5-hydroxytryptamine 1A receptor agonist on myocardial ischemia injury in rats by regulating the NLRP3/Caspase-1/GSDMD pathway

Article References: Chen, H., Li, Y., Liu, M., Chi, Y., & Zhang, L. (2026). Protection of beta-blocker and 5-hydroxytryptamine 1A receptor agonist on myocardial ischemia injury in rats by regulating the NLRP3/Caspase-1/GSDMD pathway. PLOS One, 21(10), e0360695. https://doi.org/10.1371/journal.pone.0360695

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0360695

Keywords: rat myocardial infarction, bevantolol, tandospirone, beta-blocker, 5-HT1A receptor agonist, NLRP3 inflammasome, Caspase-1, GSDMD, myocardial inflammation, pyroptosis, Protection, hydroxytryptamine

Huntington’s disease is a relentlessly progressive neurodegenerative disorder caused by an expanded CAG repeat in the Huntingtin gene, which produces a mutant protein that accumulates in neurons and exerts a toxic gain of function. The hallmark motor symptom, chorea, consists of involuntary, irregular movements that grow more severe over time and often interfere with daily activities. But the disease extends far beyond movement. Patients face progressive cognitive decline and a heavy burden of psychiatric symptoms, including anxiety and depression, with roughly twenty percent experiencing suicidal ideation. No preventive or disease-modifying therapy exists, so treatment remains purely symptomatic, and the pharmacological toolkit is thin.

The current standard of care for chorea rests on inhibitors of the vesicular monoamine transporter type 2, or VMAT2, a protein that packages monoamine neurotransmitters into synaptic vesicles. By blocking this transporter, drugs such as tetrabenazine, deutetrabenazine, and valbenazine deplete presynaptic dopamine, dampening the excess dopaminergic tone that drives chorea. This mechanism makes physiological sense: in Huntington’s disease, elevated presynaptic dopamine coincides with reduced postsynaptic D1 and D2 receptor expression on striatal neurons, so reducing dopamine release addresses the core imbalance more directly than postsynaptic dopamine receptor blockers like antipsychotics. Yet the same dopamine depletion carries a steep price. These drugs can precipitate or worsen depression, suicidality, akathisia, parkinsonism, and somnolence, and tetrabenazine carries a black box warning in the United States and is contraindicated in patients with depression or suicidal ideation in Europe.

SOM3355 emerged from an unusual route. SOM Biotech, the Spanish company behind the drug, identified bevantolol hydrochloride, a mild beta-1 blocker with thirty years of clinical use and cumulative exposure in more than 2.5 million people, through its proprietary artificial intelligence platform SOMAI PRO as a VMAT2 inhibitor. Subsequent pharmacological characterisation revealed a profile that distinguishes it from tetrabenazine in three ways. Its interaction with the VMAT2 binding site differs, producing monoamine signalling changes with a similar effect on dopamine but a significantly weaker effect on serotonin, roughly ten-fold lower serotonin affinity than tetrabenazine. It also inhibits VMAT1, a transporter tetrabenazine does not touch, and it retains beta-1 adrenergic blockade, a property that lipophilic beta-blockers have used to treat anxiety, irritability, agitation, memory disorders, and akathisia in other neuropsychiatric conditions.

The SOMCT03 trial was designed to test whether this polypharmacology translates into clinical benefit. It was a double-blind, randomised, placebo-controlled, dose-ranging study in which adults with genetically confirmed Huntington’s disease and a baseline Total Maximal Chorea score of at least ten were allocated in a one-to-one-to-one ratio to SOM3355 400 mg per day, SOM3355 600 mg per day, or placebo. The primary endpoint was the change in Total Maximal Chorea score, measured on the Unified Huntington’s Disease Rating Scale, between baseline and the end of the maintenance dose period, analysed with a mixed-effect model for repeated measures. The trial also broke new ground by incorporating Huntington’s-specific safety endpoints, including the Problem Behaviour Assessment-short form for behavioural symptoms, alongside scales for depression, sleepiness, and akathisia, aiming to define the drug’s profile beyond chorea alone.

The headline result was complicated by a phenomenon familiar to anyone who follows clinical trials: a strikingly strong placebo response. In the full modified intention-to-treat population, neither dose separated significantly from placebo on the primary endpoint, with the 600 mg per day dose showing a least-squares mean difference of minus 1.0 points and the 400 mg dose minus 0.2 points. Placebo patients improved by up to 2.3 points, roughly twice what the investigators had anticipated, possibly reflecting expectation effects and the unusually extensive contact with healthcare professionals in a disease with few effective treatments available in Europe.

However, the picture changed in the predefined sensitivity analysis restricted to the 122 patients, eighty-eight percent of the cohort, who were not taking concomitant antipsychotics, which act as dopamine receptor blockers and confound the assessment of any dopaminergic agent. In this subgroup, the 600 mg per day dose achieved a statistically significant reduction in chorea compared with placebo, with a least-squares mean difference of minus 1.3 points. A post-hoc analysis of the 57 patients who were both antipsychotic-free and had baseline chorea scores above twelve, corresponding to the upper mild range and more comparable to populations in other VMAT2 inhibitor trials, showed an even stronger effect, with chorea scores falling by 4.5 points at the final on-treatment visit and a placebo-adjusted difference of minus 1.8 points. These figures sit comfortably alongside the phase 3 results for valbenazine and deutetrabenazine, which produced placebo-adjusted differences of minus 3.2 and minus 2.5 points respectively.

Crucially, the numeric improvements were echoed by global clinical impressions. On the Clinical Global Impression of Change, seventy percent of patients on 400 mg per day and fifty-six percent on 600 mg per day were rated as improved at the final visit, compared with thirty-seven percent on placebo, and in the antipsychotic-free subgroup with higher baseline chorea, seventy-four percent of patients on the higher dose were rated improved versus twenty-one percent on placebo. Patient-rated impressions told the same story. The investigators argue that this convergence between score reductions and validated global measures of real-world change demonstrates that the observed effects are clinically meaningful to both patients and physicians, a point they intend to address directly in the design of the upcoming phase 3 study.

The safety findings may prove to be the trial’s most consequential contribution. Eighty-four percent of participants completed the study, most adverse events were mild and judged unrelated to treatment, and there were no deaths. The most notable drug-related event was bradycardia, an expected consequence of beta-1 blockade, reported in twelve percent of patients on the higher dose and leading to discontinuation in a handful of cases; heart rate reduction plateaued at around fifteen beats per minute at the 400 mg dose with no further decline at 600 mg. Blood pressure changes remained within normal limits and no QT interval prolongation was observed. More striking was what did not happen: no suicidality or suicide attempts occurred on the Columbia-Suicide Severity Rating Scale among drug-treated patients, the Beck Depression Inventory score actually fell by three points in the 600 mg arm, the Epworth Sleepiness and Montreal Cognitive Assessment scales showed no negative effects, and the Barnes Akathisia Rating Scale detected no emergence of akathisia in any group. The behavioural assessment even hinted at mild improvements in anxiety, apathy, and certain abnormal behaviours.

The trial has limitations the authors acknowledge candidly. Concomitant antipsychotic use confounded the primary analysis, the final visit assessments in the high-dose arm were performed during dose down-titration at lower plasma concentrations, the largely white European cohort limits generalisability, and the protocol did not follow sex and gender equity reporting guidelines. Still, the overall picture is of a drug that matches existing VMAT2 inhibitors on chorea control in the patients most relevant to such treatment, while eliminating the psychiatric and motor liabilities that constrain current therapy. A double-blind, placebo-controlled phase 3 study of SOM3355 at 600 mg per day is planned to confirm efficacy and long-term safety across the disease course. If it succeeds, a fifty-year-old antihypertensive, resurrected by an algorithm, could become the first chorea treatment that Huntington’s patients can take without trading away their mood, their sleep, or their peace of mind.

Subject of Research: A phase 2b trial of the repurposed beta-blocker SOM3355 for treating chorea in Huntington's disease

Article Title: Safety and efficacy of SOM3355 in patients with Huntington’s disease (SOMCT03): a phase 2b, randomised, placebo-controlled, multicentre, dose-ranging study

Article References: Kulisevsky, J., Craufurd, D., Lewerenz, J., Scaglione, C., Squitieri, F., Youssov, K., Burgunder, J.-M., Ferré, A., Panigone, S., & Medori, R. (2026). Safety and efficacy of SOM3355 in patients with Huntington’s disease (SOMCT03): a phase 2b, randomised, placebo-controlled, multicentre, dose-ranging study. eClinicalMedicine, 100, Article 104234. https://doi.org/10.1016/j.eclinm.2026.104234

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104234

Keywords: Huntington's disease, chorea, SOM3355, bevantolol, VMAT2 inhibitor, drug repurposing, clinical trial, neurodegeneration, psychiatric safety, phase 2b, tetrabenazine, artificial intelligence drug discovery