Fragile X syndrome (FXS) is the primary hereditary cause of intellectual disability and autism spectrum disorder. It is characterized by exacerbated neuronal excitability, and its correction is considered an objective measure of treatment response in animal models, a marker albeit rarely used in clinical trials. Here, we used an extensive transcranial magnetic stimulation (TMS) battery to assess the neurophysiological effects of a therapy combining two disease-modifying drugs, lovastatin (40 mg) and minocycline (100 mg), administered alone for 8 weeks and in combination for 12 weeks, in 19 patients (mean age of 23.58 ± 1.51) with FXS taking part in the LOVAmix trial. The TMS battery, which included the resting motor threshold, short-interval intracortical inhibition, long-interval intracortical inhibition, corticospinal silent period, and intracortical facilitation, was completed at baseline after 8 weeks of monotherapy (visit 2 of the clinical trial) and after 12 weeks of dual therapy (visit 4 of the clinical trial). Repeated measure ANOVAs were performed between baseline and visit 2 (monotherapy) and visit 3 (dual therapy) with interactions for which monotherapy the participants received when they began the clinical trial. Results showed that dual therapy was associated with reduced cortical excitability after 20 weeks. This was reflected by a significant increase in the resting-motor threshold after dual therapy compared to baseline. There was a tendency for enhanced short-intracortical inhibition, a marker of GABAa-mediated inhibition after 8 weeks of monotherapy compared to baseline. Together, these results suggest that a combined therapy of minocycline and lovastatin might act on the core neurophysiopathology of FXS. This trial was registered at clinicaltrials.gov (NCT02680379).

Familial Alzheimer\'s disease (FAD) presenilin 1 E280A (PSEN1 E280A) is a severe neurological condition due to the loss of cholinergic neurons (ChNs), accumulation of amyloid beta (Aβ), and abnormal phosphorylation of the TAU protein. Up to date, there are no effective therapies available. The need for innovative treatments for this illness is critical. We found that minocycline (MC, 5 μM) was innocuous toward wild-type (WT) PSEN1 ChLNs but significantly (i) reduces the accumulation of intracellular Aβ by -69%, (ii) blocks both abnormal phosphorylation of the protein TAU at residue Ser202/Thr205 by -33% and (iii) phosphorylation of the proapoptotic transcription factor c-JUN at residue Ser63/Ser73 by -25%, (iv) diminishes oxidized DJ-1 at Cys106-SO3 by -29%, (v) downregulates the expression of transcription factor TP53, (vi) BH-3-only protein PUMA, and (vii) cleaved caspase 3 (CC3) by -33, -86, and -78%, respectively, compared with untreated PSEN1 E280A ChLNs. Additionally, MC increases the response to ACh-induced Ca2+ influx by +92% in mutant ChLNs. Oxygen radical absorbance capacity (ORAC) and ferric ion-reducing antioxidant power (FRAP) analysis showed that MC might operate more efficiently as a hydrogen atom transfer agent than a single electron transfer agent. In silico molecular docking analysis predicts that MC binds with high affinity to Aβ (Vina Score -6.6 kcal/mol), TAU (VS -6.5 kcal/mol), and caspase 3 (VS -7.1 kcal/mol). Taken together, our findings suggest that MC demonstrates antioxidant, anti-amyloid, and anti-apoptosis activity and promotes physiological ACh-induced Ca2+ influx in PSEN1 E280A ChLNs. The MC has therapeutic potential for treating early-onset FAD.

Chronic stress-related brain disorders are widespread and debilitating, causing lasting neurobehavioral deficits. Minocycline, a common antibiotic and an established inhibitor of microglia, emerges as potential treatment of these disorders. The zebrafish (Danio rerio) is an important emerging model organism in translational neuroscience and stress research. Here, we evaluated the potential of minocycline to correct microglia-mediated behavioral, genomic and neuroimmune responses induced by chronic unpredictable stress (CUS) in adult zebrafish. We demonstrated that CUS evoked overt behavioral deficits in the novel tank, light-dark box and shoaling tests, paralleled by elevated stress hormones (CRH, ACTH and cortisol), upregulated brain expression of the \'neurotoxic M1\' microglia-specific biomarker gene (MHC-2) and pro-inflammatory cytokine genes (IL-1β, IL-6 and IFN-γ). CUS also elevated peripheral pro-inflammatory (IL-1β, IFN-γ), lowered anti-inflammatory cytokines (IL-4 and IL-10) and increased brain dopamine and serotonin turnover. In contrast, minocycline attenuated most of these effects, also reducing CUS-elevated peripheral levels of IL-6 and IFN-γ. Collectively, this implicates microglia in zebrafish responses to chronic stress, and suggests glial pathways as potential evolutionarily conserved drug targets for treating stress-evoked neuropathogenesis. Our findings also further support the growing translational value of zebrafish models for understanding complex molecular mechanisms of brain pathogenesis and its therapy.

Influenza A virus (IAV) poses a global threat worldwide causing pandemics, epidemics, and seasonal outbreaks. Annual modification of vaccines is costly due to continual shifts in circulating genotypes, leading to inadequate coverage in low- and middle-income countries like India. Additionally, IAVs are evolving resistance to approved antivirals, necessitating a search for alternative treatments. In this study, the antiviral role of the FDA-approved antibiotic minocycline against IAV strains was evaluated in vitro and in vivo by quantifying viral gene expression by qRT-PCR, viral protein levels by Western blotting, and viral titers. Our findings demonstrate that minocycline at a non-toxic dose effectively inhibits IAV replication, regardless of viral strain or cell line. Its antiviral mechanism operates independently of interferon signaling by targeting the MEK/ERK signaling pathway, which is crucial for the export of viral ribonucleoproteins (vRNPs). Minocycline prevents the assembly and release of infectious viral particles by causing the accumulation of vRNPs within the nucleus. Moreover, minocycline also inhibits IAV-induced late-stage apoptosis, further suppressing viral propagation. The antiviral activity of minocycline against IAVs could offer a promising solution amidst the challenges posed by influenza and the limitations of current treatments.

Antibiotics with significant environmental toxicity, e.g., tetracyclines (TCs), are often used in large quantities worldwide, with 50-80% of the applied dose ending up in the environment. This study aimed to investigate the effects of exposure to tetracycline hydrochloride (TC) and minocycline hydrochloride (MIN) on L. minor. Our research evaluated the phytotoxicity of the TCs by analyzing plant growth and biomass and evaluating assimilation pigment levels and fluorescence. The research was extended with the ability potential of duckweed as a tool for removing TCs from water/wastewater. The results demonstrated that both TCs influenced Ir, Iy, biomass, and photosynthetic efficiency. The uptake of TC and MIN by duckweed was proportional to the concentration in the growth medium. The TC was absorbed more readily, reaching up to 8.09 mg × g-1 of dry weight (DW) at the highest concentration (19.2 mg × L-1), while MIN reached 6.01 mg × g-1 of DW. As indicated, the consequences of the influence of TC on plants were slightly smaller, in comparison to MIN, while the plants could biosorb this drug, even at the lowest tested concentration. This study has shown that using plants for drug biosorption can be an effective standalone or complementary method for water and wastewater treatment.

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BACKGROUND: High fructose consumption increases blood pressure through microglia-related neuroinflammation in rats. Since intermediate-conductance calcium-activated potassium channels (KCa3.1) potentiates microglial reactivity, we examined whether the pretreatment with the KCa3.1 channel blocker TRAM-34 or minocycline prevents hypertension development in fructose-fed rats.
METHODS: The study involved male Wistar rats that were given either a high fructose (10% in drinking water) or a tap water for 21 days. Fructose groups also received minocycline or TRAM-34 systemically for 21 days. We measured systolic and diastolic blood pressure (SBP and DBP), heart rate (HR) periodically with tail-cuff; proinflammatory cytokines and insulin levels in plasma via ELISA, and neuroinflammatory markers in the nucleus tractus solitarii (NTS) by qPCR at the end of 21 days. We also examined endothelium-dependent hyperpolarization (EDH)-type vasorelaxations in isolated mesenteric arteries of the rats ex vivo.
RESULTS: SBP, DBP, and HR increased in the fructose group. Both minocycline and TRAM-34 significantly prevented these increases. Fructose intake also increased plasma IL-6, IL-1β, TNF-α, and insulin levels, whereas pretreatment with TRAM-34 prevented these increases as well. Iba-1, but not CD86 levels were significantly higher in the NTS samples of fructose-fed hypertensive rats which implied microglial proliferation. EDH-type vasorelaxations mediated by endothelial KCa3.1 attenuated in the fructose group; however, TRAM-34 did not cause further deterioration in the relaxations.
CONCLUSIONS: TRAM-34 is as effective as minocycline in preventing fructose-induced hypertension without interfering with the EDH-type vasodilation. Furthermore, TRAM-34 relieves high fructose-associated systemic inflammation.

Cardiovascular diseases remains leading cause of death and disabilities. Coronary artery occlusion and consequent ischemia leads to acute myocardial infarction, but restoration of blood flow, paradoxically, provokes further myocardial damage known as reperfusion injury. Minocycline is possessing anti-inflammatory and anti-apoptotic activity, immune-modulating and antioxidative properties besides its primary antibacterial effect. Recently it gained significant interest in preventing cardiac damage especially due to myocardial ischemia/reperfusion injury (MI/RI). The aim of this study was to assess the protective ability of pre-treatment and post-treatment of isolated hearts from healthy and spontaneously hypertensive rats with minocycline, on functional recovery and redox status after MI/RI using Langendorff technique. Using sensor in the left ventricle, the cardiodynamic parameters were recorded and in the samples of the coronary venous effluent oxidative stress biomarkers were analyzed. Minocycline was injected directly into the coronary vessels, in pre-treatment 5 min before global ischemia, and in post-treatment during the first 5 min of reperfusion. Changes in redox balance induced by minocycline were more prominent in post-treatment fashion of application. Cardioprotective effects of minocycline due to MI/RI are even more significant in hypertensive hearts. Minocycline showed significant cardioprotective effects, which was more pronounced in hypertensive compared to healthy hearts. Reduction of pro-oxidative biomarkers was more prominent in hypertensive hearts compared to the normotensive, especially if it is applied in the form of post-treatment. Minocycline could be important tool in reduction of heart damage induced by MI/RI due to its antioxidative potential, if these results are confirmed by clinical study.

Chronic stress increases activity of the brain\'s innate immune system and impairs function of the medial prefrontal cortex (mPFC). However, whether acute stress triggers similar neuroimmune mechanisms is poorly understood. Across four studies, we used a Syrian hamster model to investigate whether acute stress drives changes in mPFC microglia in a time-, subregion-, and social status-dependent manner. We found that acute social defeat increased expression of ionized calcium binding adapter molecule 1 (Iba1) in the infralimbic (IL) and prelimbic (PL) and altered the morphology Iba1+ cells 1, 2, and 7 days after social defeat. We also investigated whether acute defeat induced tissue degeneration and reductions of synaptic plasticity 2 days post-defeat. We found that while social defeat increased deposition of cellular debris and reduced synaptophysin immunoreactivity in the PL and IL, treatment with minocycline protected against these cellular changes. Finally, we tested whether a reduced conditioned defeat response in dominant compared to subordinate hamsters was associated with changes in microglia reactivity in the IL and PL. We found that while subordinate hamsters and those without an established dominance relationships showed defeat-induced changes in morphology of Iba1+ cells and cellular degeneration, dominant hamsters showed resistance to these effects of social defeat. Taken together, these findings indicate that acute social defeat alters microglial morphology, increases markers of tissue degradation, and impairs structural integrity in the IL and PL, and that experience winning competitive interactions can specifically protect the IL and reduce stress vulnerability.

Polysaccharides like hyaluronan (HA) and chondroitin sulfate (CS) are native of the brain\'s extracellular matrix crucial for myelination and brain maturation. Despite extensive research on HA and CS as drug delivery systems (DDS), their high water solubility limits their application as drug carriers. This study introduces an injectable DDS using aldehyde-modified hyaluronic acid (HAOX) hydrogel containing polyelectrolyte complexes (PEC) formed with calcium, gelatin, and either CS or aldehyde-modified CS (CSOX) to deliver minocycline for Multiple Sclerosis therapy. PECs with CSOX enable covalent crosslinking to HAOX, creating immobilized PECs (HAOX_PECOX), while those with CS remain unbound (HAOX_PECS). The in situ forming DDS can be administered via a 20 G needle, with rapid gelation preventing premature leakage. The system integrates into an implanted device for minocycline release through either Fickian or anomalous diffusion, depending on PEC immobilization. HAOX_PECOX reduced burst release by 88 %, with a duration of 127 h for 50 % release. The DDS exhibited an elastic modulus of 3800 Pa and a low swelling ratio (0-1 %), enabling precise control of minocycline release kinetics. Released minocycline reduced IL-6 secretion in the Whole Blood Monocytes Activation Test, suggesting that DDS formation may not alter the biological activity of the loaded drug.