This study aims to investigate the mechanism of acacetin in protecting rats from cerebral ischemia-reperfusion injury via the Toll-like receptor 4(TLR4)/NOD-like receptor protein 3(NLRP3) signaling pathway. Wistar rats were randomized into sham, model, low-and high-dose acacetin, and nimodipine groups, with 10 rats in each group. The rat model of middle cerebral artery occlusion(MCAO) was established with the improved suture method in other groups except the sham group. The neurological deficit score and cerebral infarction volume of each group were evaluated 24 h after modeling. Enzyme-linked immunosorbent assay(ELISA) was employed to measure the levels of interleukin-1β(IL-1β), IL-6, tumor necrosis factor-α(TNF-α), malondialdehyde(MDA), supe-roxide dismutase(SOD), and glutathione(GSH). Western blot was employed to determine the expression levels of B-cell lymphonoma-2(Bcl-2), Bcl-2-associated X protein(Bax), and TLR4/NLRP3 signaling pathway-related proteins(TLR4, p-NF-κB/NF-κB, NLRP3, pro-caspase-1, cleaved caspase-1, pro-IL-1β, and cleaved IL-1β) in the rat brain tissue. Hematoxylin-eosin(HE) staining was employed to reveal the histopathological changes in the ischemic area. Compared with the sham group, the modeling of MCAO increased the neurological deficit score and cerebral infarction volume, elevated the IL-1β, IL-6, TNF-α, and MDA levels and lowered the SOD and GSH levels in the brain tissue(P<0.05). Compared with the MCAO model group, low-and high-dose acacetin and nimodipine decreased the neurological deficit score and cerebral infarction volume, lowered the IL-1β, IL-6, TNF-α, and MDA levels and elevated the SOD and GSH levels in the brain tissue(P<0.05). Compared with the sham group, the model group showed up-regulated protein levels of Bax, TLR4, p-NF-κB/NF-κB, NLRP3, pro-caspase-1, cleaved caspase-1, pro-IL-1β, and cleaved IL-1β and down-regulated protein level of Bcl-2 in the brain tissue(P<0.05). Compared with the MCAO model group, the acacetin and nimodipine groups showed down-regulated protein levels of Bax, TLR4, p-NF-κB/NF-κB, NLRP3, pro-caspase-1, cleaved caspase-1, pro-IL-1β, and cleaved IL-1β and up-regulated protein level of Bcl-2 in the brain tissue(P<0.05). In conclusion, acacetin regulates the TLR4/NLRP3 signaling pathway to inhibit neuroinflammatory response and oxidative stress, thus exerting the protective effect on cerebral ischemia-reperfusion injury in rats.
Rats ; Animals ; NF-kappa B/metabolism* ; bcl-2-Associated X Protein ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Rats, Sprague-Dawley ; Caspase 1/metabolism* ; Toll-Like Receptor 4/metabolism* ; Nimodipine/pharmacology* ; Interleukin-6 ; Rats, Wistar ; Signal Transduction ; Infarction, Middle Cerebral Artery ; Reperfusion Injury/prevention & control* ; Superoxide Dismutase/metabolism*

To study the protective effect of Ershiwuwei Zhenzhu Pills on ischemic stroke rats. Ninety 4-weeks-old SPF male SD rats were randomly divided into 6 groups(n=15):sham operation group, model group, nimodipine group(12 mg·kg~(-1)), Ershiwuwei Zhenzhu Pills high-dose group(400 mg·kg~(-1)), Ershiwuwei Zhenzhu Pills medium-dose group(200 mg·kg~(-1)), Ershiwuwei Zhenzhu Pills low-dose group(100 mg·kg~(-1)).The permanent middle cerebral artery occlusion model(PMCAO) was established in the model group, nimodipine group, and Ershiwuwei Zhenzhu Pills groups by the improved thread plug method, while the sham operation group did not insert the thread plug.Nimodipine group and Ershiwuwei Zhenzhu Pills groups were given intragastric administration once a day for 24 days before the modeling operation, and once 1 hour before the modeling operation, while sham operation group and model group were given equal volumes of distilled water.The neuroethology of the surviving rats was measured; The volume of cerebral infarction in rats was measured by TTC method; The histopathology of rat brain was observed by HE method; The expression levels of tumor necrosis factor α(TNF-α),interleukin-1β(IL-1β),interleukin-6(IL-6),malondialdehyde(MDA),superoxide dismutase(SOD) and catalase(CAT) in serum were detected by ELISA;The mRNA expressions of Notch 1,Jagged 1,Hes 1 and Bcl-2 in rat brain were detected by RT-PCR;Western blot was used to detect the expression levels of caspase-3 protein in rat brain; the expression levels of vascular endothelial growth factor(VEGF) and CD34 positive cells in rat brain were detected by immunofluorescence.The low, medium and high dose groups of Ershiwuwei Zhenzhu Pills and nimodipine group could significantly reduce the neurobehavioral score and cerebral infarction volume of rats with permanent middle cerebral artery occlusion, reduce the morphological changes of nerve cells, decrease the expression of TNF-α,IL-1β and IL-6 in rat serum, increase the activity of SOD and CAT,and reduce the level of MDA.Furthermore, the expression levels of Notch l, Jagged l, Hes l and Bcl-2 mRNA were significantly increased, and the expression level of caspase-3 protein was decreased.Meanwhile, the number of VEGF and CD34 positive cells increased in the treatment group.The differences were statistically significant. Ershiwuwei Zhenzhu Pills has a protective effect on ischemic stroke rats, and its mechanism may be related to anti-inflammation, anti-oxidation, promotion of nerve cell proliferation, inhibition nerve cell apoptosis and promotion of angiogenesis.
Animals ; Caspase 3/metabolism* ; Drugs, Chinese Herbal/pharmacology* ; Infarction, Middle Cerebral Artery/drug therapy* ; Interleukin-6/metabolism* ; Ischemic Stroke/drug therapy* ; Male ; Nimodipine/pharmacology* ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; RNA, Messenger ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Vascular Endothelial Growth Factor A/metabolism*

Objective To explore the pharmacokinetics of nimodipine in plasma of rats after intraocular administration.Methods Totally 135 SD rats were randomly divided into three groups according to drug administration routes:intraocular(io group),intravenous (iv group),and intragastric (ig group). The doses were 5.0 mg/kg for IO and IV groups and 10.0 mg/kg for IG group. The serum nimodipine level was analyzed by high performance liquid chromatography. The main pharmacokinetic parameters were calculated and compared.Results The pharmacokinetic parameters in io group were as follows:C:0.52 mg/ml;t:5.0 min;and AUC:21.10 mg/(ml·min). The main pharmacokinetic parameters in iv group were as follows:C:3.62 mg/ml;and AUC:52.58 mg/(ml·min). The main pharmacokinetic parameters in ig group were as follows:C:0.20 mg/ml;t:5.0 min;and AUC:5.98 mg/(ml·min).Conclusions Nimodipine is rapidly absorbed after io administration,and the ophthalmic formulation has a higher bioavailability than the oral solution. Therefore,the io route may help to improve the treatment effectiveness of cardiovascular diseases.
Administration, Intravenous ; Administration, Oral ; Animals ; Area Under Curve ; Biological Availability ; Chromatography, High Pressure Liquid ; Nimodipine ; pharmacokinetics ; Rats ; Rats, Sprague-Dawley

A 50-year-old woman reported to the emergency department with thunderclap headache and vomiting. Non-enhanced brain computed tomography (CT) showed a subarachnoid hemorrhage of Hunt-Hess Grade II and Fisher Grade III. Brain angiography CT and transfemoral cerebral angiography (TFCA) revealed an aneurysm of the anterior communicating artery. A direct neck clipping was performed using the pterional approach. The post-operation CT was uneventful. Six days postoperatively, the patient became lethargic. The mean velocity (cm/s) of the middle cerebral artery peaked at 173 cm/s on the right side and 167 cm/s on the left. A TFCA revealed decreased perfusion in both recurrent arteries of Heubner (RAH), but no occlusion in either. Intra-arterial nimodipine injection was administered. On the 7th postoperative day, CT demonstrated a newly developed low-density lesion in the RAH territory bilaterally. The cause of the infarction was attributed to decreased perfusion caused by cerebral vasospasm. The patient was discharged with no definite neurologic deficit except for mild cognitive disorder.
Aneurysm ; Angiography ; Arteries* ; Brain ; Cerebral Angiography ; Emergency Service, Hospital ; Female ; Headache Disorders, Primary ; Humans ; Infarction* ; Infarction, Anterior Cerebral Artery ; Intracranial Aneurysm* ; Middle Aged ; Middle Cerebral Artery ; Neck ; Neurologic Manifestations ; Nimodipine ; Perfusion ; Subarachnoid Hemorrhage ; Vasospasm, Intracranial ; Vomiting

A comprehensive collection of proteins senses local changes in intracellular Ca²⁺ concentrations ([Ca²⁺](i) and transduces these signals into responses to agonists. In the present study, we examined the effect of sphingosine-1-phosphate (S1P) on modulation of intracellular Ca²⁺ concentrations in cat esophageal smooth muscle cells. To measure [Ca²⁺](i) levels in cat esophageal smooth muscle cells, we used a fluorescence microscopy with the Fura-2 loading method. S1P produced a concentration-dependent increase in [Ca²⁺](i) in the cells. Pretreatment with EGTA, an extracellular Ca²⁺ chelator, decreased the S1P-induced increase in [Ca²⁺](i), and an L-type Ca²⁺-channel blocker, nimodipine, decreased the effect of S1P. This indicates that Ca²⁺ influx may be required for muscle contraction by S1P. When stimulated with thapsigargin, an intracellular calcium chelator, or 2-Aminoethoxydiphenyl borate (2-APB), an InsP₃ receptor blocker, the S1P-evoked increase in [Ca²⁺](i) was significantly decreased. Treatment with pertussis toxin (PTX), an inhibitor of G(i)-protein, suppressed the increase in [Ca²⁺](i) evoked by S1P. These results suggest that the S1P-induced increase in [Ca²⁺](i) in cat esophageal smooth muscle cells occurs upon the activation of phospholipase C and subsequent release of Ca²⁺ from the InsP₃-sensitive Ca²⁺ pool in the sarcoplasmic reticulum. These results suggest that S1P utilized extracellular Ca²⁺ via the L type Ca²⁺ channel, which was dependent on activation of the S1P₄ receptor coupled to PTX-sensitive G(i) protein, via phospholipase C-mediated Ca²⁺ release from the InsP₃-sensitive Ca²⁺ pool in cat esophageal smooth muscle cells.
Animals ; Calcium ; Cats* ; Egtazic Acid ; Fura-2 ; Methods ; Microscopy, Fluorescence ; Muscle Contraction ; Muscle, Smooth* ; Myocytes, Smooth Muscle* ; Nimodipine ; Pertussis Toxin ; Phospholipases ; Sarcoplasmic Reticulum ; Thapsigargin ; Type C Phospholipases

OBJECTIVE: The cause of severe clinical vasospasm after aneurysmal subarachnoid hemorrhage remains unknown, despite extensive research over the past 30 years. However, the intra-arterial administration of vasodilating agents and balloon angioplasty have been successfully used in severe refractory cerebral vasospasm. MATERIALS AND METHODS: We retrospectively analyzed the data of 233 patients admitted to our institute with aneurysmal subarachnoid hemorrhage (SAH) over the past 3 years. RESULTS: Of these, 27 (10.6%) developed severe symptomatic vasospasm, requiring endovascular therapy. Vasospasm occurred at an average of 5.3 days after SAH. A total of 46 endovascular procedures were performed in 27 patients. Endovascular therapy was performed once in 18 (66.7%) patients, 2 times in 4 (14.8%) patients, 3 or more times in 5 (18.5%) patients. Intra-arterial vasodilating agents were used in 44 procedures (27 with nimodipine infusion, 17 with nicardipine infusion). Balloon angioplasty was performed in only 2 (7.4%) patients. The Average nimodipine infusion volume was 2.47 mg, and nicardipine was 3.78 mg. Most patients recovered after the initial emergency room visit. Two patients (7.4%) worsened, but there were no deaths. CONCLUSION: With advances in endovascular techniques, administration of vasodilating agents and balloon angioplasty reduces the morbidity and mortality of vasospasm after aneurysmal SAH.
Aneurysm* ; Angioplasty, Balloon ; Emergency Service, Hospital ; Endovascular Procedures ; Humans ; Mortality ; Nicardipine ; Nimodipine ; Retrospective Studies ; Subarachnoid Hemorrhage* ; Vasospasm, Intracranial

A 25-years-old woman with mandibular prognathism underwent a mandibular setback by way of mandibular sagittal split ramus osteotomy (MSSRO). After 2 days of operation, she developed difficulty of closing her right eye. The blink reflex test and motor nerve conduction study of the right orbicularis oris muscle were revealed right facial neuropathy of unknown origin and House-Brackmann facial nerve grading system (HBFNGS) grade V. For treatment, we initially prescribed oral prednisolone and nimodipine including physical therapy. The samples consisted of 11 facial nerve palsy patients caused by MSSRO and were analysed about onset of facial nerve palsy, postoperative HBFNGS, final HBFNGS, treatment method and recovery time. At 10 weeks of treatment of nimodipine, she had completely regained normal function (HBFNGS grade I) of the right facial nerve. The clinical results lead to assume a fast recovery of facial nerve function by the nimodipine medication, whereas average time of recovery is 16.32 weeks in references. Despite of the limited one patient treated, the result was very promising with respect to a faster recovery of the facial nerve function. Considering the use of nimodipine treatment for peripheral facial nerve palsy following a surgical approach with an anatomically preserved nerve can be recommended.
Blinking ; Facial Nerve Diseases ; Facial Nerve* ; Facial Paralysis ; Female ; Humans ; Mandible* ; Methods ; Neural Conduction ; Nimodipine ; Osteotomy, Sagittal Split Ramus* ; Paralysis* ; Prednisolone ; Prognathism

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by severe headaches with or without other acute neurological symptoms, and diffuse segmental constriction of cerebral arteries that resolves spontaneously within 3 months. A 44-year-old woman underwent heart transplantation due to primary amyloidosis with heart involvement. She started to have a seizure after three hours after the heart transplantation, and her consciousness was not recovered. Computed tomography and transcranial doppler sonography were used to diagnose RCVS, and contracted vessels were recovered after oral nimodipine administration.
Adult ; Amyloidosis ; Cerebral Arteries ; Consciousness ; Constriction ; Female ; Headache ; Heart Transplantation* ; Heart* ; Humans ; Nimodipine ; Seizures ; Ultrasonography, Doppler, Transcranial ; Vasoconstriction*

Excessive influx and the subsequent rapid cytosolic elevation of Ca²⁺ in neurons is the major cause to induce hyperexcitability and irreversible cell damage although it is an essential ion for cellular signalings. Therefore, most neurons exhibit several cellular mechanisms to homeostatically regulate cytosolic Ca²⁺ level in normal as well as pathological conditions. Delayed rectifier K⁺ channels (I(DR) channels) play a role to suppress membrane excitability by inducing K⁺ outflow in various conditions, indicating their potential role in preventing pathogenic conditions and cell damage under Ca²⁺-mediated excitotoxic conditions. In the present study, we electrophysiologically evaluated the response of IDR channels to hyperexcitable conditions induced by high Ca²⁺ pretreatment (3.6 mM, for 24 hours) in cultured hippocampal neurons. In results, high Ca²⁺-treatment significantly increased the amplitude of IDR without changes of gating kinetics. Nimodipine but not APV blocked Ca²⁺-induced IDR enhancement, confirming that the change of I(DR) might be targeted by Ca²⁺ influx through voltage-dependent Ca²⁺ channels (VDCCs) rather than NMDA receptors (NMDARs). The VDCC-mediated I(DR) enhancement was not affected by either Ca²⁺-induced Ca²⁺ release (CICR) or small conductance Ca²⁺-activated K⁺ channels (SK channels). Furthermore, PP2 but not H89 completely abolished I(DR) enhancement under high Ca²⁺ condition, indicating that the activation of Src family tyrosine kinases (SFKs) is required for Ca²⁺-mediated I(DR) enhancement. Thus, SFKs may be sensitive to excessive Ca²⁺ influx through VDCCs and enhance I(DR) to activate a neuroprotective mechanism against Ca²⁺-mediated hyperexcitability in neurons.
Animals ; Calcium Channels ; Cytosol ; Humans ; Kinetics ; Membranes ; Neurons* ; Nimodipine ; Protein-Tyrosine Kinases* ; Rats* ; Receptors, N-Methyl-D-Aspartate ; src-Family Kinases ; Tyrosine*

As advance care planning is taking center stage in the field of end-of-life care, various tools have been developed to aid in the often emotional and difficult decision-making process. Video decision support tools are one of the most promising means of assistance, of which the modus operandi is to provide more comprehensive and precise information of medical procedures to patients and their families, allowing them to make better informed decisions. Despite such value, some are concerned about its potential negative impact. For example, video footages of some procedures may be shocking and unpalatable to non-medical professionals, and patients and families may refuse the procedures. One approach to soften the sometimes unpleasant visual of medical procedures is to show less aggressive or more relaxing scenes. Yet another potential issue is that the objectivity of video decision support tools might be vulnerable to the very stakeholders who were involved in the development. Some might argue that having multiple stakeholders may function as checks and balances and provide collective wisdom, but we should provide more systematic guarantee on the objectivity of the visual decision aids. Because the decision of the modality of an individual's death is the last and most significant choice in one's life, no party should exert their influence on such a delicate decision. With carefully designed video decision support tools, our patients will live the last moments of their lives with dignity, as they deserve.
Advance Care Planning* ; Decision Making ; Decision Support Systems, Clinical ; Decision Support Techniques ; Hope* ; Humans ; Lifting* ; Nimodipine ; Palliative Care ; Shock ; Terminal Care ; Videotape Recording