AIMTo investigate the effect of nimodipine (NM) on cerebral blood flow (CBF) in dogs following intranasal administration.

METHODSNM solution was administered intranasally, intravenously (i.v.), and orally to dogs and the change of CBF was determined by using electromagnetic blood flowmeter. MFLab experimental program was applied to monitor the experimental process and analyze data.

RESULTSCBF markedly increased after iv and intranasal application, while large variance was observed after oral dosing. CBF in dogs after three administrations increased by 26.4%, 28.0% and 8.5%, respectively, compared with that of baseline. Following intranasal administration, the onset of action was slightly slower than that after iv injection [(5 +/- 4) min vs (2.2 +/- 1.2) min], however the duration of improvement was the longest [ (25 +/- 17) min].

CONCLUSIONIntranasal delivery for NM can be a promising alternative to parenteral or oral administration.

Administration, Intranasal ; Administration, Oral ; Animals ; Blood Flow Velocity ; drug effects ; Cerebrovascular Circulation ; drug effects ; Dogs ; Female ; Injections, Intravenous ; Male ; Nimodipine ; administration & dosage ; pharmacology ; Vasodilator Agents ; administration & dosage ; pharmacology

OBJECTIVETo observe the effects of Tongxinluo (TXL) on angiogenesis and the volume of blood perfusion in ischemic stroke rats.

METHODSThe model of middle cerebral artery occlusion (MCAO) was established using craniotomy ligation of the middle cerebral artery on one side. After screening, the male SD rats were randomly divided into the sham-operation group, the model group, the large dose TXL group, the middle dose TXL group, the low dose TXL group, and the Nimodipine group. The expression of microvascular density (MVD, CD31) of the MCAO rats was detected using immunohistochemical assay after 14 days of medication. The microvascular morphology and the volume of blood perfusion in the brain tissue were observed under laser scanning confocal microscope (LSCM).

RESULTSThe positive CD31 expression was intense with significant coloring in the large dose TXL group, the middle dose TXL group, and the Nimodipine group, better than that of the model group. The blood perfusion volume in the ischemic brain cortex could be promoted in the large dose TXL group, the middle dose TXL group, and the Nimodipine group (P<0.01, P<0.05). The optimal effects were shown in the large dose TXL group (P<0.01).

CONCLUSIONTXL significantly increased the MVD of the ischemic brain tissue, promoted the post-ischemic angiogenesis, and increased the volume of blood perfusion of ischemic brain tissue, playing certain blood flow compensatory roles.

Animals ; Brain Ischemia ; Disease Models, Animal ; Drugs, Chinese Herbal ; pharmacology ; Hemoperfusion ; Male ; Neovascularization, Physiologic ; drug effects ; Nimodipine ; pharmacology ; Rats ; Rats, Sprague-Dawley

The aim was to study the mechanisms of HL-60 cell apoptosis induced by nimodipine (NMDP) and cytarabine (Ara-C). The DNA fragment was detected by agarose gel electrophoresis. The expressions of bcl-2 and bax gene proteins related with apoptosis were investigated by immunohistochemistry. The results showed that HL-60 cell apoptosis rate had been increasing in the experimental groups compared with the control group since culturing 8 hours. The expression of Bcl-2 protein was lower and the expression of Bax protein was higher in the experimental groups than that in the control group, while ratio of bcl-2/bax was lower in the experimental groups than that in the control group. It is concluded that NMDP and Ara-C induce apoptosis of HL-60 cells, and the mechanism of apoptosis induced by them may down-regulate the expression of bcl-2 gene and up-regulate the expression of bax gene. The mechanism of HL-60 cell apoptosis induced by Ara-C and NMDP is probably associated with the down-regulation of Bcl-2 protein expression.
Antimetabolites, Antineoplastic ; pharmacology ; Apoptosis ; drug effects ; Cytarabine ; pharmacology ; Drug Resistance, Neoplasm ; drug effects ; Drug Synergism ; Gene Expression Regulation, Neoplastic ; HL-60 Cells ; Humans ; Nimodipine ; pharmacology ; Proto-Oncogene Proteins c-bcl-2 ; biosynthesis ; genetics ; bcl-X Protein ; biosynthesis ; genetics

OBJECTIVETo explore the mechanism and type of acute infectious brain edema induced by injection of pertussis bacilli (PB) in rat neocortex, to study the neuroprotective effect of non-competitive antagonist of N-methl-D-aspartate (NMDA) receptor (MK-801) and antagonist of Ca(2+) channels (nimodipine) on brain edema, and to investigate the relationship between percentage of water content and cytosolic free calcium concentration ([Ca(2+) ](i)) in synaptosomes or content of Evans Blue (EB).

METHODS95 SD rats were randomly divided into five groups, ie, normal control group, sham-operated control group, PB group, nimodipine treatment group and MK-801 pretreatment group. The acute infectious brain edema was induced by injection of PB into the rats. Quantitative measurements of water content and the concentration of EB were performed. [Ca(2+) ](i) was determined in calcium fluorescent indication Fura-2/AM loaded neuronal synaptosome with a spectrofluorophotometer. To observe the effect of MK-801 and nimodipine, we administered MK-801 48 hours and 24 hours before the injection of PB in MK-801 pretreatment group, and nimodipine after the injection of PB in nimodipine treatment group. The specific binding of NMDA receptor was measured with [(3)H]-MK-801 in the neuronal membrane of cerebral cortex.

RESULTSThe levels of water content and EB content of brain tissues, and [Ca(2+) ](i) in the neuronal synaptosomes increased more significantly in the PB-injected cerebral hemisphere in the PB group than those of normal control group and sham-operated control group (P<0.05). The water content and [Ca(2+) ](i) increased with the duration of infectious brain edema. Nimodipine administered after the injection of PB could significantly decrease the water content, EB and [Ca(2+) ](i) (P<0.05). MK-801 could significantly decrease the water content, EB and [Ca(2+) ](i) in 4 h and 24 h groups (P<0.05). The Kd values were 30.5 nmol/L+/-3.0 nmol/L and 42.1 nmol/L+/-4.2 nmol/L in PB group and NS group respectively (P<0.05), and Bmax were 0.606 pmol/mg.pro+/-0.087 pmol/mg.pro and 0.623 pmol/mg.pro+/-0.082 pmol/mg.pro respectively, without statistical significance (P>0.05).

CONCLUSIONSThe changes in the permeability of blood-brain barrier (BBB) and Ca(2+)-overload may participate in the pathogenesis of infectious brain edema. Treatment with nimodipine can dramatically reduce the damage of brain edema and demonstrate neuroprotective effect on brain edema by inhibiting the excess of Ca(2+) influx and reducing the permeability of BBB. MK-801 pretreatment may inhibit the delayed Ca(2+) influx into the neurons. The infectious brain edema is not only cytotoxic brain edema (intracellular edema) but also vasogenic brain edema (extracellular edema) followed by earlier BBB breakdown, so infectious brain edema is complicated with brain edema.

Acute Disease ; Analysis of Variance ; Animals ; Blood-Brain Barrier ; drug effects ; Bordetella pertussis ; Brain Edema ; drug therapy ; metabolism ; microbiology ; Calcium ; metabolism ; Calcium Channel Blockers ; pharmacology ; Dizocilpine Maleate ; pharmacology ; Nimodipine ; pharmacology ; Rats ; Rats, Sprague-Dawley

In order to explore whether the member of Bcl-2 gene family, for example, Bcl-2 and Bax, are induced after cerebral ischemia, and whether expression of genes can be modulated by calcium-antagonist, the rat cerebral ischemic models were made by occluding left middle cerebral artery. The expression of Bcl-2 and Bax mRNA was measured by RT-PCR method. After middle cerebral artery occlusion (MCAO), the expression of both Bcl-2 and Bax mRNA were induced. Level of Bcl-2 mRNA increased steadily and level of Bax mRNA increased gradually at first, reached a peak after 24 h, then decreased slowly. After administration of nimodipine, Bcl-2 mRNA was up-regulated in the hippocampus 6 and 24 h after ischemia, while Bax mRNA was down-regulated 6 and 24 h after ischemia. Focal cerebral ischemia can induce proto-oncogenes to express, which was associated with apoptosis. Calcium-antagonist can up-regulate Bcl-2 mRNA and down-regulate Bax mRNA. The increased ratio of Bcl-2 and Bax mRNA may contribute to the anti-apoptic effect of nimodipine. The study indicates that pharmacological modulation of Bcl-2 family member expression could become a new strategy to manage neuronal damage.
Animals ; Apoptosis ; drug effects ; Brain Ischemia ; metabolism ; Calcium Channel Blockers ; pharmacology ; Nimodipine ; pharmacology ; Proto-Oncogene Proteins c-bcl-2 ; biosynthesis ; genetics ; RNA, Messenger ; biosynthesis ; genetics ; Rats ; Rats, Wistar ; bcl-2-Associated X Protein ; biosynthesis ; genetics

AIMTo build a simple and repeatable animal model of subarachnoid hemorrhage (SAH).

METHODSSAH was produced by passing a nylon thread up through the right internal carotid artery and piercing a hole in the right anterior cerebral artery. At 12 h and 24 h after SAH operation, the rats were evaluated with rotarod test and the behavior scale (5-point scale).

RESULTSThe rats were trained through rotarod test and then randomly divided into three groups, including vehicle group treated with vehicle after SAH, nimodipine treated group (i.p. 0.25 mg x kg(-1), 5 min, 6 h, 12 h after SAH) and sham group. At the point of the perforation there was usually a capping clot. There was always blood in the basal cisterns with some spread over the hemisphere. After 12 h and 24 h of SAH operation, the time of rotarod test of rats decreased significantly and the rats had serious neurological deficit. Nimodipine could alleviate the neurological deficit after 24 h of SAH.

CONCLUSIONTo present a simple and reliable model of SAH in the rats, which allows evaluating novel compounds and new drugs for treatment of SAH.

Animals ; Behavior, Animal ; drug effects ; Brain ; pathology ; Calcium Channel Blockers ; pharmacology ; Cerebrovascular Circulation ; drug effects ; Disease Models, Animal ; Male ; Nimodipine ; pharmacology ; Rats ; Rats, Wistar ; Reproducibility of Results ; Rotarod Performance Test ; Subarachnoid Hemorrhage ; etiology ; pathology ; physiopathology

OBJECTIVETo study the therapeutic effect of nimodipine on experimental brain injury.

METHODSExperimental and control rabbits were subjected to a closed head injury. In one group nimodipine was given intravenously and the effect evaluated by electron microscopy, brain water content, calcium levels, transcranial Doppler, and intracranial pressure monitoring.

RESULTSIn rabbits treated with nimodipine the level of neuronal cytosolic free calcium was markedly decreased. There were less cellular damage and less spasm of the middle cerebral artery seen on electron microscopy. No difference regarding intracranial pressure changes between the two groups was noted.

CONCLUSIONSNimodipine has a protective action on brain injury by blocking a series of pathological reactions induced by neuronal calcium overload, and by reducing the spasm of brain vessels and improving cerebral blood flow.

Animals ; Biopsy, Needle ; Brain Edema ; prevention & control ; Brain Injuries ; drug therapy ; pathology ; Calcium Channel Blockers ; pharmacology ; Disease Models, Animal ; Female ; Immunohistochemistry ; Infusions, Intravenous ; Male ; Nimodipine ; pharmacology ; Probability ; Rabbits ; Reference Values ; Sensitivity and Specificity ; Statistics, Nonparametric

2-Amino-5-phosphonovalerate ; pharmacology ; Animals ; Animals, Newborn ; Cells, Cultured ; Cerebral Cortex ; cytology ; physiology ; Hydrogen-Ion Concentration ; Hypothermia, Induced ; Neurons ; drug effects ; Nimodipine ; pharmacology ; Protons ; Random Allocation ; Rats ; Rats, Wistar

OBJECTIVETo explore changes of neuronal calcium channel following brain damage induced by injection of pertussis bacilli in rats, and to investigate the relationship between cytosolic free calcium concentration ([Ca(2+)](i)) in the synaptosome and Ca(2+)-ATPase activities of mitochondria.

METHODSThe level of [Ca(2+)](i) in the synaptosome and Ca(2+)-ATPase activities of mitochondria in the acute brain damage induced by injection of pertussis bacilli (PB) in rat was determined and nimodipine was administrated to show its effects on [Ca(2+)](i) in the synaptosome and on alteration of Ca(2+)-ATPase activity in the mitochondria. Seventy-three rats were randomly divided into four groups, ie, normal control group (Group A), sham-operation control group (Group B), PB group (Group C) and nimodipine treatment group (Group D).

RESULTSThe level of [Ca(2+)](i) was significantly increased in the PB-injected cerebral hemisphere in the Group C as compared with that in the Group A and the Group B at 30 minutes after injection of PB. The level of [Ca(2+)](i) was kept higher in the 4 hours and 24 hours subgroups after the injection in the Group C (P<0.05). In contrast, the Ca(2+)-ATPase activities were decreased remarkably among all of the subgroups in the Group C. Nimodipine, which was administered after injection of PB, could significantly decrease the [Ca(2+)](i) and increase the activity of Ca(2+)-ATPase (P<0.05).

CONCLUSIONSThe neuronal calcium channel is opened after injection of PB. There is a negative correlation between activities of Ca(2+)-ATPase and [Ca(2+)](i). Nimodipine can reduce brain damage through stimulating the activities of Ca(2+)-ATPase in the mitochondria, and decrease the level of [Ca(2+)](i) in the synaptosome. Treatment with nimodipine dramatically reduces the effects of brain damage induced by injection of PB.

Analysis of Variance ; Animals ; Bordetella pertussis ; Brain Injuries ; metabolism ; Calcium ; metabolism ; Calcium Channel Blockers ; pharmacology ; Calcium-Transporting ATPases ; metabolism ; Cytosol ; metabolism ; Mitochondria ; enzymology ; Nimodipine ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Synaptosomes ; metabolism

OBJECTIVETo study the effects of calcium and calmodulin dependent kinase against hypoxic neuronal injury and its possible mechanisms.

METHODSEmbryonic cortical neurons of 17-day pregnant embryo Sprague-Dawley rats were cultured in vitro and the cultured neurons were randomly allocated into different groups that exposed to hypoxia or hypoxia +calcium channel antagonist. Nimodipine and MK-801 were used to block the L-voltage sensitive calcium channel and NMDA receptor respectively before hypoxia. The methyl thiazolyl tetrazolium (MTT) method was used to determine the cell viability. Fluo-4AM, an intracellular calcium indictor, was used to detect the changes of intracellular calcium after hypoxia. The expressions of CaMKII and CaMKIV were detected by Western blot.

RESULTSThe cell viability of the nimodipine or MK-801-treated groups was significantly higher than that of the untreated hypoxia group. The intracellular calcium level of the nimodipine-treated group decreased rapidly after hypoxia. Compared to nimodipine treatment, MK-801 treatment could inhibit hypoxia-induced calcium influx for a longer time. Nimodipine treatment decreased the CaMKII expression while MK-801 treatment decreased the CaMKIV expression.

CONCLUSIONSNimodipine and MK-801 protect neurons from hypoxic injury possibly by the inhibition of CaMKII and CaMKIV expressions respectively.

Animals ; Calcium ; analysis ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 ; Calcium-Calmodulin-Dependent Protein Kinase Type 4 ; Calcium-Calmodulin-Dependent Protein Kinases ; antagonists & inhibitors ; physiology ; Cell Hypoxia ; Dizocilpine Maleate ; pharmacology ; Female ; Neurons ; pathology ; Neuroprotective Agents ; pharmacology ; Nimodipine ; pharmacology ; Rats ; Rats, Sprague-Dawley