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BACKGROUND: Thyroid eye disease (TED) is a vision-threatening autoimmune disorder. Orbital tissue fibrosis leading to intractable complications remains a troublesome issue in TED management. Exploration of novel therapeutic targets and agents to ameliorate tissue fibrosis is crucial for TED. Recent work suggests that Ca2+ signaling participates in tissue fibrosis. However, whether an alteration of Ca2+ signaling has a role in fibrogenesis during TED remains unclear. In this study, we aimed to investigate the role of Ca2+ signaling in the fibrogenesis process during TED and the potential therapeutic effects of a highly selective inhibitor of the L-type calcium channel (LTCC), nimodipine, through a TGF-ß1 induced in vitro TED model. METHODS: Primary culture of orbital fibroblasts (OFs) were established from orbital adipose connective tissues of patients with TED and healthy control donors. Real-time quantitative polymerase chain reaction (RT-qPCR) and RNA sequencing were used to assess the genes expression associated with LTCC in OFs. Flow cytometry, RT-qPCR, 5-ethynyl-2'-deoxyuridine (EdU) proliferation assay, wound healing assay and Western blot (WB) were used to assess the intracellular Ca2+ response on TGF-ß1 stimulation, and to evaluate the potential therapeutic effects of nimodipine in the TGF-ß1 induced in vitro TED model. The roles of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and signal transducer and activator of transcription 1 (STAT1) in fibrogenesis during TED were determined by immunohistochemistry, WB, flow cytometry and co-immunoprecipitation assay. Selective inhibitors were used to explore the downstream signaling pathways. RESULTS: LTCC inhibitor nimodipine blocked the TGF-ß1 induced intracellular Ca2+ response and further reduced the expression of alpha-smooth muscle actin (α-SMA), collagen type I alpha 1 (Col1A1) and collagen type I alpha 2 (Col1A2) in OFs. Besides, nimodipine inhibited cell proliferation and migration of OFs. Moreover, our results provided evidence that activation of the CaMKII/STAT1 signaling pathway was involved in fibrogenesis during TED, and nimodipine inhibited the pro-fibrotic functions of OFs by down-regulating the CaMKII/STAT1 signaling pathway. CONCLUSIONS: TGF-ß1 induces an LTCC-mediated Ca2+ response, followed by activation of CaMKII/STAT1 signaling pathway, which promotes the pro-fibrotic functions of OFs and participates in fibrogenesis during TED. Nimodipine exerts potent anti-fibrotic benefits in vitro by suppressing the CaMKII/STAT1 signaling pathway. Our work deepens our understanding of the fibrogenesis process during TED and provides potential therapeutic targets and alternative candidate for TED.
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Calcium channel blockers (CCBs) are commonly used in the management of multiple diseases, including hypertension, arrhythmia, and vasospastic disorder. Nimodipine, a dihydropyridine CCB, has demonstrated utility in preserving hearing following vestibular schwannoma resection surgery. Due to its widespread use, CCB overdose is common. This case report presents a unique case of CCB toxicity in a 56-year-old female with end-stage liver dysfunction. The patient developed vasodilatory shock after receiving a single dose of prophylactic nimodipine following vestibular schwannoma surgery. The primary objective of this report is to highlight the unique risk for CCB toxicity that exists for patients with advanced liver disease who receive nimodipine in the perioperative setting.
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BACKGROUND AND PURPOSE: Vasospasm is a common iatrogenic event during mechanical thrombectomy (MT). In such circumstances, intra-arterial nimodipine administration is occasionally considered. However, its use in the treatment of iatrogenic vasospasm during MT has been poorly studied. We investigated the impact of iatrogenic vasospasm treated with intra-arterial nimodipine on outcomes after MT for large vessel occlusion stroke. METHODS: We conducted a retrospective analysis of the multicenter observational registry Endovascular Treatment in Ischemic Stroke (ETIS). Consecutive patients treated with MT between January 2015 and December 2022 were included. Patients treated with medical treatment alone, without MT, were excluded. We also excluded patients who received another in situ vasodilator molecule during the procedure. Outcomes were compared according to the occurrence of cervical and/or intracranial arterial vasospasm requiring intraoperative use of in situ nimodipine based on operator's decision, using a propensity score approach. The primary outcome was a modified Rankin Scale (mRS) score of 0-2 at 90 days. Secondary outcomes included excellent outcome (mRS score 0-1), final recanalization, mortality, intracranial hemorrhage and procedural complications. Secondary analyses were performed according to the vasospasm location (intracranial or cervical). RESULTS: Among 13,678 patients in the registry during the study period, 434 received intra-arterial nimodipine for the treatment of MT-related vasospasm. In the main analysis, comparable odds of favorable outcome were observed, whereas excellent outcome was significantly less frequent in the group with vasospasm requiring nimodipine (adjusted odds ratio [aOR] 0.78, 95% confidence interval [CI] 0.63-0.97). Perfect recanalization, defined as a final modified Thrombolysis In Cerebral Infarction score of 3 (aOR 0.63, 95% CI 0.42-0.93), was also rarer in the vasospasm group. Intracranial vasospasm treated with nimodipine was significantly associated with worse clinical outcome (aOR 0.64, 95% CI 0.45-0.92), in contrast to the cervical location (aOR 1.37, 95% CI 0.54-3.08). CONCLUSION: Arterial vasospasm occurring during the MT procedure and requiring intra-arterial nimodipine administration was associated with worse outcomes, especially in case of intracranial vasospasm. Although this study cannot formally differentiate whether the negative consequences were due to the vasospasm itself, or nimodipine administration or both, there might be an important signal toward a substantial clinical impact of iatrogenic vasospasm during MT.
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Nimodipine is the primary clinical drug used to treat cerebral vasospasm following subarachnoid hemorrhage. Currently, tablets have low bioavailability when taken orally, and injections contain ethanol. Therefore, we investigated a new method of nimodipine administration, namely, nasoencephalic administration. Nasal administration of nimodipine was carried out by attaching the cell-penetrating peptide octa-arginine (R8) to liposomes of nimodipine and incorporating it into a temperature-sensitive in situ gel. The prepared liposomes and gels underwent separate evaluations for in vitro characterization. In vitro release exhibited a significant slow-release effect. In vitro toad maxillary cilia model, RPMI 2650 cytotoxicity, and in vivo SD rat pathological histotoxicity experiments showed that all the dosage from the groups had no significant toxicity to toad maxillary cilia, RPMI 2650 cells, and SD rat tissues and organs, and the cilia continued to oscillate up to 694 ± 10.15 min, with the survival rate of the cells being above 85%. A transwell nasal mucosa cell model and an isolated porcine nasal mucosa model were established, and the results showed that the osmolality of the R8-modified nimodipine liposomal gel to nasal mucosal cells and isolated porcine nasal mucosa was 30.41 ± 2.14 and 65.9 ± 7.34 µg/mL, respectively, which was significantly higher than that of the NM-Solution and PEGylated nimodipine liposome gel groups. Animal fluorescence imaging studies revealed that the R8-modified nimodipine liposomal gel displayed increased brain fluorescence intensity compared to the normal liposomal gel. Pharmacokinetic results showed that after transnasal administration, the AUC(0-∞) of the R8-modified nimodipine liposomal gel was 11.662 ± 1.97 µg·mL-1, which was significantly higher than that of the plain nimodipine liposomal gel (5.499 ± 2.89 µg·mL-1). Brain-targeting experiments showed that the brain-targeting efficiencies of the PEGylated nimodipine liposome gel and R8-modified PEGylated nimodipine liposome gels were 20.44 and 33.45, respectively, suggesting that R8/PEG/Lip-NM-TSG significantly increased the brain-targeting of the drug.
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The secondary injury is more serious after traumatic brain injury (TBI) compared with primary injury. Release of excessive reactive oxygen species (ROS) and Ca2+ influx at the damaged site trigger the secondary injury. Herein, a neutrophil-like cell membrane-functionalized nanoparticle was developed to prevent ROS-associated secondary injury. NCM@MP was composed of three parts: (1) Differentiated neutrophil-like cell membrane (NCM) was synthesized, with inflammation-responsive ability to achieve effective targeting and to increase the retention time of Mn3O4 and nimodipine (MP) in deep injury brain tissue via C-X-C chemokine receptor type 4, integrin beta 1 and macrophage antigen-1. (2) Nimodipine was used to inhibit Ca2+ influx, eliminating the ROS at source. (3) Mn3O4 further eradicated the existing ROS. In addition, NCM@MP also exhibited desirable properties for T1 enhanced imaging and low toxicity which may serve as promising multifunctional nanoplatforms for precise therapies. In our study, NCM@MP obviously alleviated oxidative stress response, reduced neuroinflammation, protected blood-brain barrier integrity, relieved brain edema, promoted the regeneration of neurons, and improved the cognition of TBI mice. This study provides a promising TBI management to relieve the secondary spread of damage.
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Lesiones Traumáticas del Encéfalo , Calcio , Nanopartículas , Neutrófilos , Especies Reactivas de Oxígeno , Animales , Especies Reactivas de Oxígeno/metabolismo , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/metabolismo , Ratones , Nanopartículas/química , Calcio/metabolismo , Neutrófilos/metabolismo , Neutrófilos/efectos de los fármacos , Masculino , Membrana Celular/metabolismo , Membrana Celular/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: One of the reasons for tolerance to morphine is increased oxidative stress and dysfunction of cell mitochondria in the hippocampus. Venlafaxine and calcium channel blockers can protect mitochondrial function. The investigation of the role of mitochondrial damage and oxidative stress in the simultaneous use of venlafaxine and calcium channel blockers on the acute analgesic effects of morphine and the induction of tolerance to its effects in mice was assessed. METHOD: In this experimental study, to induce tolerance to morphine, NMRI mice were treated with 50â¯mg/kg morphine for three consecutive days and 5â¯mg/kg morphine on the fourth day. Venlafaxine (20â¯mg/kg) alone or in combination with calcium channel blockers, nimodipine (10â¯mg/kg), and diltiazem (40â¯mg/kg) was administered 30â¯min before morphine, and the hot plate test was used. Then, hippocampal mitochondria were isolated by differential centrifugation method, and the levels of mitochondrial dehydrogenase activity, mitochondrial membrane potential, mitochondrial ROS production rate, as well as the content of glutathione and malondialdehyde in hippocampal mitochondria, were measured. RESULTS: The administration of venlafaxine-nimodipine and venlafaxine-diltiazem increased morphine's acute analgesic effects (Pâ¯<â¯0.05) and reduced the induction and expression of tolerance to the analgesic effects of morphine (Pâ¯<â¯0.05). Morphine significantly decreased MTT and GSH and increased MDA, mitochondrial membrane damage, and ROS compared to the control group (Pâ¯<â¯0.01). Injection of venlafaxine-nimodipine and also venlafaxine-diltiazem 30â¯min before morphine can improve these alterations (Pâ¯<â¯0.05). DISCUSSION AND CONCLUSION: Our data showed that the simultaneous use of venlafaxine with calcium channel blockers could increase the acute analgesic effects of morphine and reduce the induction and expression of tolerance to it. Also, the preventive and protective roles of simultaneous administration of venlafaxine and calcium channel blockers on morphine-induced mitochondrial oxidative stress and damage during the tolerance test were achieved.
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L-type voltage-gated calcium channels (L-VGCCs) are thought to be involved in epileptogenesis and acute excitotoxicity. However, little is known about the role of L-VGCCs in neuroinflammation or delayed neuronal death following excitotoxic insult. We examined the effects of repeated treatment with the L-VGCC blocker nimodipine on neuroinflammatory changes and delayed neuronal apoptosis in the dentate gyrus following trimethyltin (TMT)-induced convulsions. Male C57BL/6 N mice were administered TMT (2.6 mg/kg, i.p.), and the expression of the Cav1.2 and Cav1.3 subunits of L-VGCC were evaluated. The expression of both subunits was significantly decreased; however, the astroglial expression of Cav1.3 L-VGCC was significantly induced at 6 and 10 days after TMT treatment. Furthermore, astroglial Cav1.3 L-VGCCs colocalized with both the pro-inflammatory phenotype marker C3 and the anti-inflammatory phenotype marker S100A10 of astrocytes. Nimodipine (5 mg/kg, i.p. × 5 at 12-h intervals) did not significantly affect TMT-induced astroglial activation. However, nimodipine significantly attenuated the pro-inflammatory phenotype changes, while enhancing the anti-inflammatory phenotype changes in astrocytes after TMT treatment. Consistently, nimodipine reduced the levels of pro-inflammatory astrocytes-to-microglia mediators, while increasing the levels of anti-inflammatory astrocytes-to-microglia mediators. These effects were accompanied by an increase in the phosphorylation of extracellular signal-regulated kinase (ERK), supporting our previous finding that p-ERK is a signaling factor that regulates astroglial phenotype changes. In addition, nimodipine significantly attenuated TMT-induced microglial activation and delayed apoptosis of dentate granule neurons. Our results suggest that L-VGCC blockade attenuates neuroinflammation and delayed neurotoxicity following TMT-induced convulsions through the regulation of astroglial phenotypic changes by promoting ERK signaling.
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The clinical management of aneurysmal subarachnoid hemorrhage (SAH)-associated vasospasm remains a challenge in neurosurgical practice, with its prevention and treatment having a major impact on neurological outcome. While considered a mainstay, nimodipine is burdened by some non-negligible limitations that make it still a suboptimal candidate of pharmacotherapy for SAH. This narrative review aims to provide an update on the pharmacodynamics, pharmacokinetics, overall evidence, and strength of recommendation of nimodipine alternative drugs for aneurysmal SAH-associated vasospasm and delayed cerebral ischemia. A PRISMA literature search was performed in the PubMed/Medline, Web of Science, ClinicalTrials.gov, and PubChem databases using a combination of the MeSH terms "medical therapy," "management," "cerebral vasospasm," "subarachnoid hemorrhage," and "delayed cerebral ischemia." Collected articles were reviewed for typology and relevance prior to final inclusion. A total of 346 articles were initially collected. The identification, screening, eligibility, and inclusion process resulted in the selection of 59 studies. Nicardipine and cilostazol, which have longer half-lives than nimodipine, had robust evidence of efficacy and safety. Eicosapentaenoic acid, dapsone and clazosentan showed a good balance between effectiveness and favorable pharmacokinetics. Combinations between different drug classes have been studied to a very limited extent. Nicardipine, cilostazol, Rho-kinase inhibitors, and clazosentan proved their better pharmacokinetic profiles compared with nimodipine without prejudice with effective and safe neuroprotective role. However, the number of trials conducted is significantly lower than for nimodipine. Aneurysmal SAH-associated vasospasm remains an area of ongoing preclinical and clinical research where the search for new drugs or associations is critical.
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Isquemia Encefálica , Fármacos Neuroprotectores , Nimodipina , Hemorragia Subaracnoidea , Vasoespasmo Intracraneal , Humanos , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/tratamiento farmacológico , Vasoespasmo Intracraneal/tratamiento farmacológico , Vasoespasmo Intracraneal/etiología , Nimodipina/uso terapéutico , Isquemia Encefálica/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Neuroprotección/efectos de los fármacos , Cilostazol/uso terapéutico , Nicardipino/uso terapéutico , Dioxanos/uso terapéutico , Vasodilatadores/uso terapéutico , Pirimidinas/uso terapéutico , Piridinas , Sulfonamidas , TetrazolesRESUMEN
Nimodipine, a calcium antagonist, exert beneficial neurovascular protective effects in clinic. Recently, Calcium channel blockers (CCBs) was reported to protect against liver fibrosis in mice, while the exact effects of Nimodipine on liver injury and hepatic fibrosis remain unclear. In this study, we assessed the effect of nimodipine in Thioacetamide (TAA)-induced liver fibrosis mouse model. Then, the collagen deposition and liver inflammation were assessed by HE straining. Also, the frequency and phenotype of NK cells, CD4+T and CD8+T cells and MDSC in liver and spleen were analyzed using flow cytometry. Furthermore, activation and apoptosis of primary Hepatic stellate cells (HSCs) and HSC line LX2 were detected using α-SMA staining and TUNEL assay, respectively. We found that nimodipine administration significantly attenuated liver inflammation and fibrosis. And the increase of the numbers of hepatic NK and NKT cells, a reversed CD4+/CD8+T ratio, and reduced the numbers of MDSC were observed after nimodipine treatment. Furthermore, nimodipine administration significantly decreased α-SMA expression in liver tissues, and increased TUNEL staining adjacent to hepatic stellate cells. Nimodipine also reduced the proliferation of LX2, and significantly promoted high level of apoptosis in vitro. Moreover, nimodipine downregulated Bcl-2 and Bcl-xl, simultaneously increased expression of JNK, p-JNK, and Caspase-3. Together, nimodipine mediated suppression of growth and fibrogenesis of HSCs may warrant its potential use in the treatment of liver fibrosis.
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Células Estrelladas Hepáticas , Células Asesinas Naturales , Cirrosis Hepática , Hígado , Ratones Endogámicos C57BL , Nimodipina , Tioacetamida , Animales , Nimodipina/farmacología , Nimodipina/uso terapéutico , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/inmunología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/patología , Cirrosis Hepática/inmunología , Ratones , Hígado/efectos de los fármacos , Hígado/patología , Hígado/inmunología , Masculino , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/uso terapéutico , Apoptosis/efectos de los fármacos , Humanos , Modelos Animales de Enfermedad , Línea Celular , Microambiente Celular/efectos de los fármacos , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunologíaRESUMEN
This critique discusses neuroprotective strategies for aneurysmal subarachnoid hemorrhage (SAH), excluding Nimodipine, emphasizing alternatives like verapamil, albumin, and cilostazol. While these options show potential, their efficacy lacks robust confirmation from randomized controlled trials (RCTs), relying mainly on observational studies and small trials. The letter underscores the need for comprehensive safety assessments and long-term outcome studies to enhance practical application. Highlighting ongoing trials and emerging therapies like clazosentan and TAK-044, it advocates for future research directions focused on large-scale RCTs and combination therapies, such as cilostazol and Nimodipine, which have demonstrated synergistic benefits in reducing delayed cerebral ischemia (DCI) and improving patient outcomes.
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Isquemia Encefálica , Fármacos Neuroprotectores , Nimodipina , Hemorragia Subaracnoidea , Vasoespasmo Intracraneal , Humanos , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/tratamiento farmacológico , Vasoespasmo Intracraneal/tratamiento farmacológico , Vasoespasmo Intracraneal/prevención & control , Vasoespasmo Intracraneal/etiología , Nimodipina/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/prevención & control , Neuroprotección/efectos de los fármacos , Cilostazol/uso terapéuticoRESUMEN
Vasogenic brain edema, a potentially life-threatening consequence following an acute ischemic stroke, is a major clinical problem. This research aims to explore the therapeutic benefits of nimodipine, a calcium channel blocker, in mitigating vasogenic cerebral edema and preserving blood-brain barrier (BBB) function in an ischemic stroke rat model. In this research, animals underwent the induction of ischemic stroke via a 60-min blockage of the middle cerebral artery and treated with a nonhypotensive dose of nimodipine (1 mg/kg/day) for a duration of five days. The wet/dry method was employed to identify cerebral edema, and the Evans blue dye extravasation technique was used to assess the permeability of the BBB. Furthermore, immunofluorescence staining was utilized to assess the protein expression levels of matrix metalloproteinase-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1). The study also examined mitochondrial function by evaluating mitochondrial swelling, succinate dehydrogenase (SDH) activity, the collapse of mitochondrial membrane potential (MMP), and the generation of reactive oxygen species (ROS). Post-stroke administration of nimodipine led to a significant decrease in cerebral edema and maintained the integrity of the BBB. The protective effects observed were associated with a reduction in cell apoptosis as well as decreased expression of MMP-9 and ICAM-1. Furthermore, nimodipine was observed to reduce mitochondrial swelling and ROS levels while simultaneously restoring MMP and SDH activity. These results suggest that nimodipine may reduce cerebral edema and BBB breakdown caused by ischemia/reperfusion. This effect is potentially mediated through the reduction of MMP-9 and ICAM-1 levels and the enhancement of mitochondrial function.
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Barrera Hematoencefálica , Edema Encefálico , Bloqueadores de los Canales de Calcio , Accidente Cerebrovascular Isquémico , Metaloproteinasa 9 de la Matriz , Nimodipina , Animales , Nimodipina/farmacología , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/etiología , Edema Encefálico/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Masculino , Ratas , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Modelos Animales de Enfermedad , Especies Reactivas de Oxígeno/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratas Sprague-Dawley , Molécula 1 de Adhesión Intercelular/metabolismo , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/complicaciones , Dilatación Mitocondrial/efectos de los fármacos , Succinato Deshidrogenasa/metabolismoRESUMEN
Nimodipine is used to prevent delayed ischemic deficit in patients with aneurysmal subarachnoid hemorrhage (aSAH). Spreading depolarization (SD) is recognized as a factor in the pathomechanism of aSAH and other acute brain injuries. Although nimodipine is primarily known as a cerebral vasodilator, it may have a more complex mechanism of action due to the expression of its target, the L-type voltage-gated calcium channels (LVGCCs) in various cells in neural tissue. This study was designed to investigate the direct effect of nimodipine on SD, ischemic tissue injury, and neuroinflammation. SD in control or nimodipine-treated live mouse brain slices was induced under physiological conditions using electrical stimulation, or by subjecting the slices to hypo-osmotic stress or mild oxygen-glucose deprivation (mOGD). SD was recorded applying local field potential recording or intrinsic optical signal imaging. Histological analysis was used to estimate tissue injury, the number of reactive astrocytes, and the degree of microglia activation. Nimodipine did not prevent SD occurrence in mOGD, but it did reduce the rate of SD propagation and the cortical area affected by SD. In contrast, nimodipine blocked SD occurrence in hypo-osmotic stress, but had no effect on SD propagation. Furthermore, nimodipine prevented ischemic injury associated with SD in mOGD. Nimodipine also exhibited anti-inflammatory effects in mOGD by reducing reactive astrogliosis and microglial activation. The results demonstrate that nimodipine directly inhibits SD, independent of nimodipine's vascular effects. Therefore, the use of nimodipine may be extended to treat acute brain injuries where SD plays a central role in injury progression.
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Isquemia Encefálica , Encéfalo , Depresión de Propagación Cortical , Nimodipina , Animales , Nimodipina/farmacología , Ratones , Depresión de Propagación Cortical/efectos de los fármacos , Masculino , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/patología , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/patología , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/uso terapéutico , Presión Osmótica/efectos de los fármacosRESUMEN
PURPOSE: The clinical importance and management of vasospasm as a complication during endovascular stroke treatment (EVT) has not been well studied. We sought to investigate the effect of adding nimodipine to the guiding catheter flush (GCF) to prevent vasospasm during EVT. METHODS: This is a single-center retrospective analysis including patients with EVT (stent-retriever and/or distal aspiration) treated for anterior or posterior circulation intracranial vessel occlusion from January 2018 to June 2023. Exclusion criteria were intracranial or extracranial stenosis, intra-arterial alteplase, patient age over 80 years. Study groups were patients with (nimo+) and without (nimo-) nimodipine in the GCF. They were compared for occurrence of vasospasm as primary endpoint and clinical outcome in univariate analysis. RESULTS: 477 patients were included in the analysis (nimo+ nâ¯= 94 vs. nimo- nâ¯= 383). Nimo+ patients experienced less vasospasm during EVT (e.g. vasospasm in target vessel n (%): nimo-â¯= 113 (29.6) vs. nimo+â¯= 9 (9.6), pâ¯< 0.001; extracranial vasospasm, n (%): nimo-â¯= 68 (17.8) vs. nimo+â¯= 7 (7.4), pâ¯= 0.017). Patients of the two study groups had a comparable clinical outcome (90 day mRS, median (IQR): 3 (1-6) for both groups, pâ¯= 0.896). In general, patients with anterior circulation target vessel occlusion (TVO) experienced more vasospasm (anterior circ. TVO 38.7% vs. posterior circ. 7.5%, pâ¯= 0.006). CONCLUSION: Prophylactic adding of nimodipine reduces the risk of vasospasm during EVT without affecting the clinical outcome. Patients with anterior circulation TVO experienced more vasospasm compared to posterior circulation TVO.
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BACKGROUND: The prophylactic use of nimodipine following subarachnoid hemorrhage is a practice established four decades ago when clinical management differed from current and the concept of Delayed Cerebral Ischemia (DCI) was not established. The applicability of the original studies is limited by the fact of not reflecting current practice; by utilising a dichotomised outcome measure such as good neurological outcome versus death and vegetative state; by applying variable dosing regimens and including all causes of poor neurological outcome different than DCI. This study aims to review the available evidence to discuss the ongoing role of nimodipine in contemporaneous clinical practice. METHODS: PRISMA guidelines based review, evaluated the evidence on the prophylactic use of nimodipine. The following search engines: Medline, Embase, Cochrane, Web of Science and PubMed, identified Randomized Control Trials (RCTs) with neurological benefit as outcome measure and the impact of fixed versus weight-based nimodipine dosing regimens. RESULTS: Eight RCT were selected. Three of those trials with a total of 349 patients, showed a reduction on death and vegetative state (pooled RR: 0.62; 95 % confidence interval-CI: 0.45, 0.86) related to DCI. Amongst all studies, all cause death (pooled RR = 0.73, [95 % CI: 0.56, 0.97]) favoured a fixed-dose regimen (pooled RR: 0.60; [95 % CI: 0.43, 0.85]). CONCLUSION: Available evidence demonstrates that nimodipine only reduces the risk for DCI-related death or vegetative state and that fixed-dose regimens favour all cause infarct and death independent of DCI. Contemporaneous studies assessing the benefit of nimodipine beyond death or vegetative states and applying individualized dosing are warranted.
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Nimodipina , Hemorragia Subaracnoidea , Nimodipina/administración & dosificación , Nimodipina/uso terapéutico , Humanos , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/tratamiento farmacológico , Bloqueadores de los Canales de Calcio/administración & dosificación , Bloqueadores de los Canales de Calcio/uso terapéutico , Vasodilatadores/administración & dosificación , Vasodilatadores/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Sleep disorders are one of the most common acute reactions on the plateau, which can cause serious complications. However, there is no effective and safe treatment currently available. Nimodipine (NMD) is a dihydropyridine calcium channel blocker with neuroprotective and vasodilating activity, mainly used for the treatment of ischemic brain injury. Commercial oral or injectable NMD formulations are not a good option for central neuron diseases due to their poor brain delivery. In this study, nimodipine dissolving microneedles (NDMNs) were prepared for the prevention of sleep disorders caused by hypoxia. NDMNs were composed of NMD and polyvinyl pyrrolidone (PVP) K90 with a conical morphology and high rigidity. After administration of NDMNs on the back neck of mice, the concentration of NMD in the brain was significantly higher than that of oral medication as was confirmed by the fluorescent imaging on mouse models. NDMNs enhanced cognitive function, alleviated oxidative stress, and improved the sleep quality of mice with high-altitude sleep disorders. The blockage of calcium ion overloading may be an important modulation mechanism. NDMNs are a promising and user-friendly formulation for the prevention of high-altitude sleep disorders.
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Bloqueadores de los Canales de Calcio , Nimodipina , Trastornos del Sueño-Vigilia , Animales , Ratones , Nimodipina/administración & dosificación , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Trastornos del Sueño-Vigilia/prevención & control , Masculino , Bloqueadores de los Canales de Calcio/administración & dosificación , Altitud , Agujas , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Estrés Oxidativo/efectos de los fármacos , Povidona/química , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Enteral nimodipine is the most evidence-based and widely used drug for the treatment of delayed cerebral ischemia and is known to have various neuroprotective functions. However, the neuroprotective mechanism of nimodipine still remains unclear, and the effects of nimodipine remain ambiguous. Herein, we studied the effect of enteral nimodipine on endothelial apoptosis after subarachnoid hemorrhage (SAH). METHODS: SAH was experimentally introduced in white rabbits (n = 42) that were grouped as follows: enteral nimodipine (SAH-nimodipine group, n = 14), a control that received normal saline (SAH-saline group, n = 13), and a control without hemorrhage (control group, n = 15). On the third day after SAH induction, the brain stem, including the vertebrobasilar vascular system, was extracted. The effects of enteral nimodipine were analyzed by group using histopathologic analysis, including immunohistochemical staining of apoptosis-related proteins (Bcl2 [anti-apoptotic] and Bax [pro-apoptotic]). RESULTS: Cytoplasmic vacuolation of smooth muscle cells was observed in two SAH hemorrhagic groups and was more prominent in the SAH-saline group. Endothelial desquamation was observed only in the SAH-saline group. For the basilar artery, expression of Bcl2 and Bax in the SAH-nimodipine group was lower than that in the SAH-saline group, but significant differences were not observed (pBcl2 = 0.311 and pBax = 0.720, respectively). In penetrated arterioles, the expression of Bax in the SAH-nimodipine group was significantly lower than that of the SAH-saline group (p < 0.001). The thickness of the tunica media in the basilar artery was thinner in the SAH-nimodipine group than in the SAH-saline group (p < 0.001). CONCLUSIONS: This study suggests that enteral nimodipine may have a neuroprotective function by inhibiting endothelial apoptosis in small arterioles and preventing smooth muscle cell proliferation in large arteries.
Asunto(s)
Apoptosis , Modelos Animales de Enfermedad , Células Endoteliales , Nimodipina , Hemorragia Subaracnoidea , Hemorragia Subaracnoidea/tratamiento farmacológico , Animales , Nimodipina/farmacología , Apoptosis/efectos de los fármacos , Conejos , Células Endoteliales/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , MasculinoRESUMEN
The discovery of brain therapeutics faces a significant challenge due to the low translatability of preclinical results into clinical success. To address this gap, several efforts have been made to obtain more translatable neuronal models for phenotypic screening. These models allow the selection of active compounds without predetermined knowledge of drug targets. In this review, we present an overview of various existing models within the field, examining their strengths and limitations, particularly in the context of neuropathic pain research. We illustrate the usefulness of these models through a comparative review in three crucial areas: i) the development of novel phenotypic screening strategies specifically for neuropathic pain, ii) the validation of the models for both primary and secondary screening assays, and iii) the use of the models in target deconvolution processes.
Asunto(s)
Neuralgia , Humanos , Neuralgia/tratamiento farmacológico , EncéfaloRESUMEN
In recent years, researchers have shown a growing interest in the interactions between different pharmaceutical agents. An intriguing instance lies in the possible interaction between nimodipine and vitamin C. To investigate the pharmacokinetic and pharmacodynamic effects of vitamin C on nimodipine in rats, rats were randomly divided into a nimodipine only group and a combination group (nimodipine + vitamin C). The two groups were given intragastric administration and nimodipine blood concentrations were determined using high-performance liquid chromatography-tandem mass spectrum at different time points. Blood pressure and heart rate were measured via carotid artery cannulation. Pharmacokinetic differences were observed between the nimodipine only group and the combination group at the same dose. Compared with the nimodipine only group, the combination group's main pharmacokinetic parameters of peak concentration and area under the curve increased significantly, and the difference was statistically significant (p < 0.05); furthermore, the combination group exhibited a significant reduction in average blood pressure, while no significant effects on heart rate were observed. Vitamin C did not affect the activity of CYP450 in rat liver. The pharmacokinetic characteristics and pharmacodynamics of nimodipine were changed by vitamin C administration in rats.
Asunto(s)
Ácido Ascórbico , Nimodipina , Ratas , Animales , Cromatografía Líquida de Alta Presión , Sistema Enzimático del Citocromo P-450RESUMEN
Nimodipine dose reduction is recommended in case of high vasopressor demand after aneurysmal subarachnoid hemorrhage (aSAH). The aim of this study was to assess potential adverse effects of nimodipine reduction during the high-risk period for delayed cerebral ischemia (DCI) and cerebral vasospasm (CVS) between days 5 and 10 after hemorrhage. Demographic and clinical data as well as daily nimodipine dose of aSAH patients admitted between 2010 and 2019 were retrospectively analyzed. Univariable and multivariable regression analyses were performed to identify factors associated with DCI, angiographic CVS, DCI-related infarction, and unfavorable outcome. A total of 205 patients were included. Nimodipine dose reduction occurred in 108 (53%) patients ('nimodipine reduction group'), while 97 patients (47%) received the full dose ('no nimodipine reduction group'), Patients in the 'nimodipine reduction group' had significant worse WFNS and Fisher grades and developed significantly more often DCI and angiographic CVS. DCI-related infarction and unfavorable outcome were also significantly increased in the 'nimodipine reduction group.' 'Reduced nimodipine dose' was the only independent predictor for the occurrence of DCI and angiographic CVS in multivariable regression analysis. 'Poor WFNS grade' and 'reduced nimodipine dose' were identified as independent risk factors for DCI-related infarction while 'older age,' 'poor WFNS grade,' and 'reduced nimodipine dose' were associated with unfavorable outcome at 3 months after discharge. Nimodipine dose reduction during the high-risk period of DCI and CVS between days 5 and 10 after hemorrhage might abrogate the positive prognostic effects of nimodipine and should be critically evaluated.
Asunto(s)
Hemorragia Subaracnoidea , Vasoespasmo Intracraneal , Humanos , Nimodipina/uso terapéutico , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/tratamiento farmacológico , Hemorragia Subaracnoidea/cirugía , Reducción Gradual de Medicamentos , Estudios Retrospectivos , Infarto Cerebral/tratamiento farmacológico , Infarto Cerebral/etiología , Vasoespasmo Intracraneal/tratamiento farmacológico , Vasoespasmo Intracraneal/etiologíaRESUMEN
BACKGROUND: Causes of morbidity and mortality following aneurysmal subarachnoid hemorrhage (aSAH) include early brain injury and delayed neurologic deterioration, which may result from delayed cerebral ischemia (DCI). Complex pathophysiological mechanisms underlie DCI, which often includes angiographic vasospasm (aVSP) of cerebral arteries. METHODS: Despite the study of many pharmacological therapies for the prevention of DCI in aSAH, nimodipine-a dihydropyridine calcium channel blocker-remains the only drug recommended universally in this patient population. A common theme in the research of preventative therapies is the use of promising drugs that have been shown to reduce the occurrence of aVSP but ultimately did not improve functional outcomes in large, randomized studies. An example of this is the endothelin antagonist clazosentan, although this agent was recently approved in Japan. RESULTS: The use of the only approved drug, nimodipine, is limited in practice by hypotension. The administration of nimodipine and its counterpart nicardipine by alternative routes, such as intrathecally or formulated as prolonged release implants, continues to be a rational area of study. Additional agents approved in other parts of the world include fasudil and tirilazad. CONCLUSIONS: We provide a brief overview of agents currently being studied for prevention of aVSP and DCI after aSAH. Future studies may need to identify subpopulations of patients who can benefit from these drugs and perhaps redefine acceptable outcomes to demonstrate impact.