Batenac (mibefradil) / Jazz - LARVOL DELTA

Integrative analysis of signaling and metabolic pathways, immune infiltration patterns, and machine learning-based diagnostic model construction in major depressive disorder. (PubMed, Sci Rep) - "Through GSEA scoring, five upregulated pathways in the high-risk MDD group were identified, and multiple potential drugs such as Mibefradil, LY364947, ZLN005, STA- 5326, and vemurafenib were screened. By constructing an MDD diagnostic model, we predicted the key genes of MDD and the characteristic pathways associated with a higher risk of MDD. This provides new insights for risk stratification identification and offers new perspectives for the clinical application of precision immunotherapy and drug development."

Journal • CNS Disorders • Depression • Inflammation • Major Depressive Disorder • Mood Disorders • Psychiatry

Targeting Ion Channels: Blockers Suppress Calcium Signals and Induce Cytotoxicity Across Medulloblastoma Cell Models. (PubMed, Bioengineering (Basel)) - "Spontaneous calcium signals were significantly reduced by mibefradil (calcium channel blocker), paxilline (calcium-activated potassium channel blocker), and thioridazine (potassium channel blocker)...In contrast, digoxin and ouabain, inhibitors of the Na/K pump, reduced the calcium signaling by over 90% in DAOY cells and induced approximately 90% cell death in DAOY cells and 80% cell death in D283 cells. However, these effects were significantly diminished in the cells derived from a patient with MB, highlighting the variability in drug sensitivity among MB models. These findings demonstrate that calcium signaling is critical for MB cell survival and that the targeted inhibition of calcium pathways suppresses tumor cell growth across multiple MB models."

Journal • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor

T-type calcium channels attenuate anxiety in MPTP-treated mice through modulating burst firing of dopaminergic neuron. (PubMed, Neuropharmacology) - "In the present study, we constructed Parkinson's disease (PD) model mice using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and we found that intracerebroventricular injection of T-VGCC blocker (Mibefradil) alleviates the anxiety behavior and the extent of damage to DAergic neurons in MPTP-treated mice...To sum up, our research results for the first time reveal the crucial role that the burst firing of DAergic neurons in the SN mediated by T-VGCC plays in regulating anxiety behavior in PD. This discovery offers a potential therapeutic target for PD patients with anxiety."

Journal • Preclinical • CNS Disorders • Mood Disorders • Movement Disorders • Parkinson's Disease • Psychiatry

T-type calcium channels regulate medulloblastoma and can be targeted for therapy. (PubMed, J Neurooncol) - "Our results represent a first comprehensive multi-omic characterization of T-type calcium channels in medulloblastoma and provide preclinical data for repurposing mibefradil as a treatment strategy for these relatively common pediatric brain tumors."

Journal • Brain Cancer • Medulloblastoma • Oncology • Pediatrics • Solid Tumor

Voltage-Gated Calcium Channels and the Parity-Dependent Differential Uterine Response to Oxytocin in Rats. (PubMed, Reprod Sci) - "Dose-inhibition responses to mibefradil (TTCC inhibitor) and verapamil (LTCC inhibitor) were conducted on isolated V and PB uterine strips. Our findings suggest that TTCCs play a more important role than LTCC in the parity-dependent differential response to oxytocin. The impact of ORAI and TRP channels still needs to be evaluated, to gain a more comprehensive understanding of the relative impact of voltage-gated calcium channels vs. storage-operated calcium entry channels on this phenomenon."

Journal • Preclinical

Microenvironment T-Type calcium channels regulate neuronal and glial processes to promote glioblastoma growth. (PubMed, bioRxiv) - "The Cav3 blocker drug mibefradil synergized with temozolomide (TMZ) and radiation to reduce in vivo tumor growth and prolong animal survival. Conclusions Together these data reveal a role for microenvironment Cav3 in promoting GBM tumor progression through regulating neuronal and glial processes particularly associated with the OPC-cell state. Targeting both intrinsic and microenvironment Cav3 with the inhibitor mibefradil significantly enhanced the anti-GBM effects of TMZ and radiation."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CAV3 • OLIG2 • SOX10

The role of LHb T-type calcium channel in the neuropathic pain-depression comorbidity (IASP 2024) - "Mibefradil was used to observe the changes of LHb neurons excitability and the functional of T-type calcium channels in electrophysiological experiments... The SNC model can cause the occurrence of NP-depression comorbidity and the T-type calcium channel of LHb neurons is an ion channel which involved in the formation of NP-depression comorbidity and the regulation of pain and depression. T-type calcium channel is an important target for the treatment of NP-depression comorbidity."

CNS Disorders • Depression • Mood Disorders • Neuralgia • Pain • Psychiatry

Advancing Cardiovascular Drug Screening Using Human Pluripotent Stem Cell-Derived Cardiomyocytes. (PubMed, Int J Mol Sci) - "We found that cardiotoxic drugs withdrawn due to adverse drug reactions, including encainide, mibefradil, and cetirizine, exhibited toxicity in hPSC-CMs but not in HEK293-hERG cells. The observed changes in calcium dynamics following drug exposure demonstrated the utility of hPSC-CMs as a versatile model system for assessing both cardiotoxicity and drug efficacy. Overall, our findings highlight the potential of hPSC-CMs in advancing drug discovery and development, which offer a physiologically relevant platform for the preclinical screening of novel therapeutics."

Journal • Cardiovascular

ROLE OF L- AND T-TYPE VOLTAGE-DEPENDENT CALCIUM CHANNELS IN THE HIERARCHICAL ORGANIZATION OF DEFENSIVE RESPONSES TO ELECTRICAL STIMULATION OF THE RAT DORSOLATERAL PERIAQUEDUCTAL GRAY. (PubMed, Neuropharmacology) - "Accordingly, here we investigated the effects of microinjection of lower doses (0.7 and 7 nmol) of both verapamil and mibefradil, a preferential blocker of T-type calcium channels, on DPAG-evoked defensive behaviors of the male rat. While galloping was not attenuated by either antagonist, jumping was unexpectedly attenuated by 0.7 nmol verapamil only. These results suggest that T-type calcium channels are involved in the low-threshold freezing responses of exophthalmia and immobility, whereas L-type calcium channels are involved in the trotting response that precedes the full-fledged escape responses of galloping and jumping."

Journal • Preclinical • Ophthalmology

Lavandula angustifolia Mill. inhibits high glucose and nicotine-induced Ca2+ influx in microglia and neuron-like cells via two distinct mechanisms. (PubMed, Biomed Pharmacother) - "Ca2+ influx in neuron-like cells pretreated with HG plus nicotine was also significantly decreased by LEO, an effect partially inhibited by the L-type Ca2+ channel blocker nifedipine and the T-type Ca2+ channel blocker mibefradil. LEO or a two-fold increase in the applied number of astrocytes attenuated Ca2+ influx caused by high glucose and nicotine in the mixed cells of the microglia, neuron-like cells and astrocytes. These findings suggest that LEO can regulate HG and nicotine-induced Ca2+ influx into microglia and neurons through two distinct mechanisms."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Cav3.2 channel regulates cerebral ischemia/reperfusion injury: a promising target for intervention. (PubMed, Neural Regen Res) - "T-type calcium channel blockers, such as pimozide and mibefradil, have been shown to prevent cerebral ischemia/reperfusion injury-induced brain injury. These findings suggest that the neuroprotective function of Cav3.2 knockout is mediated by calcineurin/nuclear factor of activated T cells 3 signaling. Findings from this study suggest that Cav3.2 could be a promising target for treatment of cerebral ischemia/reperfusion injury."

Journal • Cardiovascular • CNS Disorders • Diabetes • Inflammation • Reperfusion Injury • Vascular Neurology • CAV3 • NFATC1 • NFATC3

Analgesic Buxus alkaloids with Enhanced Selectivity for the Low-Voltage-Gated Calcium Channel Cav3.2 over Cav3.1 through a New Binding Mode. (PubMed, Angew Chem Int Ed Engl) - "Animal studies in wild-type and Cav3.2 knock-out mice revealed that BXSL (5 mg/kg), by inhibiting Cav3.2, exhibits an analgesic effect equivalent to Z944 (10 mg/kg) or mibefradil (10 mg/kg). Moreover, we proposed a structural rationale for 9(10/19)abeo-artane-type alkaloids towards their high selectivity of Cav3.2 over Cav3.1. This study introduces a novel analgesic agent and valuable molecular insights for structure-based innovative Cav3.2 drug development."

Journal • CNS Disorders • Epilepsy • Essential Tremor • Movement Disorders • Pain • CAV3

Modulation of FDG Uptake by Cell Cycle Synchronization Using a T-Type Calcium Channel Inhibitor. (PubMed, Cancers (Basel)) - "Cell cycle synchronization could be used to increase the diagnostic sensitivity of clinical FDG positron emission tomography."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Combination treatment of calcium channel antagonist mibefradil enhances the effect of hydroxyurea at therapeutic ranges in high-grade meningioma in vitro. (SNO 2023) - "FDA-approved VGCC antagonists nimodipine (NIMO) and mibefradil (MIB) target two different VGCCs, L- and T-type channels, and have been of great interest for their use in combination therapy in other cancers...We cultured CH-157MN and IOMM-Lee MN cells and assessed their cell survival, apoptosis, and proliferation in the presence of temozolomide, octreotide, sunitinib, or hydroxyurea (HU)...Here we demonstrate for the first time that T-type calcium channels play an important role in MN survival. The combination of HU and MIB suggests their use could be a promising treatment for high-grade MN."

Preclinical • Brain Cancer • CNS Tumor • Meningioma • Oncology • Solid Tumor

T-Type Calcium Channels regulate neuron-glioblastoma interactions and promote tumor growth (SNO 2023) - "To complement publicly available data,we treated Glioblastoma Stem cells (GSCs) with an FDA-approved repurposed TTCC blocker, mibefradil, and found downregulation of genes associated with neuron processes such as synapse organization, postsynaptic density and glutamatergic synapses...Transcriptomic analysis of tumors from Cav3.2KO tumors revealed deregulation of genes associated synaptic transmission, glutamatergic synapses and postsynaptic specialization. Altogether, our findings indicate a role of Cav3.2 in regulating tumors and neurons and promoting GBM progression."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CAV3 • SLC2A1

Cav3.2 T-type calcium channel mediates acute itch and contributes to chronic itch and inflammation in experimental atopic dermatitis. (PubMed, J Invest Dermatol) - "Genetic knockout of Cav3.2 or T-type calcium channel blocker mibefradil treatment reduced spontaneous and mechanically induced scratching behaviors and skin inflammation in an AD-like mouse model...Our study identifies the role of Cav3.2 in both histaminergic and non-histaminergic acute itch. Cav3.2 channel also contributes to AD-related chronic itch and neuroinflammation."

Journal • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation • Pain • CAV3 • IL13 • IL4 • TSLP

CAV3.2 T-TYPE CALCIUM CHANNEL MEDIATES ACUTE ITCH AND CONTRIBUTES TO CHRONIC ITCH AND NEUROINFLAMMATION IN EXPERIMENTAL ATOPIC DERMATITIS (ISAD 2023) - "Genetic knockout of Cav3.2 or T-type calcium channel blocker mibefradil treatment significantly reduced spontaneous and mechanically induced scratching behaviors and skin inflammation in an AD-like mouse model...Our study identifies the role of Cav3.2 channel in both histaminergic and non-histaminergic itch pathways. Cav3.2 channel also contributes to AD-related chronic itch and neuroinflammation."

Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation • Pain • IL13 • IL4 • TSLP

Pulmonary Microcirculation in Experimental Model of Pulmonary Thromboembolism after Pretreatment with Chloroquine. (PubMed, Bull Exp Biol Med) - "The increase in the pulmonary vascular resistance and pre- and postcapillary resistance was less pronounced than after pulmonary thromboembolism after pretreatment with mibefradil (T-type Ca channels blocker) or nifedipine (L-type Ca channels blocker). When modeling pulmonary thromboembolism after pretreatment with chloroquine combined with glibenclamide (K channels blocker), the studied hemodynamics parameters increased to the same extent as after pretreatment with nifedipine. The results indicate that chloroquine exhibits the properties of an L- and T-type Ca channels blocker and an activator of K channels."

Journal • Cardiovascular • Pulmonary Embolism

Impact of Heterotropic Allosteric Modulation on the Time-Dependent Inhibition of CYP3A4. (PubMed, Drug Metab Dispos) - "The presence of varying concentrations of testosterone, progesterone (PGS), or carbamazepine (CBZ) in HLMs with MDZ could recapitulate the effect of homotropic cooperativity such that the formation rates of the 1'hydroxymidazolam and 4-hydroxymidazolam were equal even at low concentrations of MDZ. The presence of PGS (10 or 100 µM) and CBZ (100 or 1000 µM) in in vitro TDI determination of four known CYP3A4 time-dependent inactivators (clarithromycin, troleandomycin, mibefradil, raloxifene) simultaneously decreased potency and inactivation rate constant, resulting in fold changes in inactivation efficiency on average of 1.6-fold and 13-fold for the low and high concentrations of allosteric modulator tested respectively...We provide characterization of allosteric modulators on the CYP3A4 metabolism of the prototypical substrate midazolam, demonstrating the ability of the modulators to recapitulate the homotropic cooperativity of midazolam. Furthermore, we..."

Journal • CYP3A4

Cell Surface Vibrations Distinguish Malignant from Benign Cells. (PubMed, Cells) - "Blocking T-type Ca-channels using Mibefradil reduced cortical actin tension in these cells and enhanced their membrane vibrations and dissipation of intracellular mechanical work to the cell surroundings...Our results show that cell membrane vibrations and dissipation of mechanical work are higher in malignant cells relative to benign cells. Accordingly, these properties may be used to detect and monitor cellular and tissue malignancies."

Journal • Bladder Cancer • Hematological Malignancies • Leukemia • Melanoma • Oncology • Solid Tumor

Two-pore channel 1 and Ca release-activated Ca channels contribute to the acrosomal pH-dependent intracellular Ca increase in mouse sperm. (PubMed, J Physiol) - "Mibefradil (Mib) and NNC 55-0396 (NNC) are two amphipathic weak bases that block the sperm-specific Ca channel (CatSper) and induce acrosomal pH (pH ) increase by accumulating in the acrosomal lumen of mammalian sperm...TPC1 and CRAC channels contribute to [Ca ] elevation during acrosomal alkalinization. Our findings expand our understanding of how the acrosomal pH participates in the physiological induction of the AR."

Journal • Preclinical

CACNA1D overexpression and voltage-gated calcium channels in prostate cancer during androgen deprivation. (PubMed, Sci Rep) - "Cells were treated with anti-androgen drug, Enzalutamide (ENZ) or androgen-removal from media, mimicking androgen-deprivation therapy (ADT)...ADT or ENZ-treated LNCaP exhibited nifedipine-sensitive Ca-transients; ADT-treated LNCaP exhibited mibefradil-sensitive or, occasionally, nifedipine-sensitive inward currents...Hormone therapy enables depolarization/Bay K-evoked Ca-transients and detection of Ca1.3 and Ca3.2 currents. Physiological and genomic CACNA1D/Ca1.3 mechanisms are likely active during hormone therapy-their modulation may offer therapeutic advantage."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Integration of reconfigurable microchannels into aligned three-dimensional neural networks for spatially controllable neuromodulation. (PubMed, Sci Adv) - "We demonstrated the spatiotemporally resolved neuromodulation in an aligned 3D neural network by local deliveries of KCl and Ca signal inhibitors, such as tetrodotoxin, nifedipine, and mibefradil, and also visualized Ca signal propagation with a speed of ~3.7 μm/s. We anticipate that our technology will pave the way to elucidate functional connectivity and neurological diseases associated with transsynaptic propagation."

Journal • CNS Disorders

Hexane fraction of Prunus japonica thunb. Seed extract enhances boar sperm motility via CatSper ion channel. (PubMed, Heliyon) - "The increase in intracellular calcium levels was inhibited when the sperm were treated with a CatSper (cation channel of sperm) channel inhibitor, 10 μM Mibefradil, indicating the involvement of the ion channel in the PJE modulatory mechanism...Our observations further elaborate ion channel-related underlying mechanisms and show putative implications of the seed extract of traditionally used P. japonica Thunb. in ameliorating sperm quality."

Journal

L- and T-type Ca channels dichotomously contribute to retinal ganglion cell injury in experimental glaucoma. (PubMed, Neural Regen Res) - "These changes were blocked by the tumor necrosis factor-α inhibitor XPro1595, indicating that both types of Ca currents may be mediated by soluble tumor necrosis factor-α. TUNEL assays revealed that mibefradil, a T-type calcium channel blocker, reduced the number of apoptotic retinal ganglion cells in the rat model of chronic ocular hypertension. These results suggest that T-type Ca channels are involved in disrupted Ca homeostasis and apoptosis of retinal ganglion cells in glaucoma, and application of T-type Ca channel blockers, especially a specific Ca3.3 blocker, may be a potential strategy for the treatment of glaucoma."

Journal • Cardiovascular • Eye Cancer • Glaucoma • Oncology • Ophthalmology