Calcium Antagonist Nimodipine Research Articles

Intravenous Nimodipine Treatment for Severe Episode of ATP1A2 Hemiplegic Migraine

Abstract Hemiplegic migraine (HM) is a rare, genetically heterogenous migraine subtype with aura presenting as recurrent transient attacks of hemicrania and hemiparesis. There are no established evidence-based guidelines for the emergency management of HM, and acute therapy therefore remains empiric. We report for the first time a successful treatment of a prolonged Na+-K+-ATPase subunit gene ATP1A2 -linked HM attack in a pediatric case with the calcium antagonist nimodipine. Nimodipine treatment is currently established only for management of HM involving calcium channels. Our results suggest that nimodipine can be an effective emergency treatment option for HM devoid of calcium channel pathologies, arguing for suggested effects of nimodipine such as the inhibition of cerebral vasoconstriction.

Multiple Actions of Phencyclidine and (+)MK-801 on Isolated Bovine Cerebral Arteries.

This study examines the direct effects of 3 noncompetitive N-methyl-D-aspartate receptor antagonists, phencyclidine (PCP), (+)MK-801, and (-)MK-801, on bovine middle cerebral arteries (BMCA). Rings of BMCA were mounted in isolated tissue chambers equipped with isometric tension transducers to obtain pharmacologic dose-response curves. In the absence of endogenous vasoconstrictors, the 3 N-methyl-D-aspartate antagonists each produced direct constriction of BMCA. The thromboxane A2 receptor antagonist SQ-29,548, the TxA2 synthase inhibitor furegrelate, the calcium antagonist nimodipine, and calcium-deficient media all inhibited maximal phencyclidine or (+)MK-801-induced constriction. Direct constriction by PCP or (+)MK-801 was independent of the presence of endothelium. When BMCA were preconstricted with potassium-depolarizing solution, PCP, (+)MK-801, and (-)MK-801 each produced only concentration-dependent relaxation. When BMCA were preconstricted with the stable TxA2 analog U-46,619 and exposed to increasing concentrations of PCP, (+)MK-801, or (-)MK-801, tension increased. Thromboxane A2 may contract BMCA by acting as a potassium channel blocker; iberiotoxin and tetraethylammonium both constrict BMCA. In Ca-deficient media containing either potassium or U-46,619, phencyclidine and (+)MK-801 each produced competitive inhibition of subsequent Ca-induced constriction. In additional experiments, arterial strips were mounted in isolated tissue chambers to directly measure calcium uptake, using Calcium as a radioactive tracer. Both phencyclidine and (+)MK-801 blocked potassium-stimulated or U-46,619-stimulated Ca uptake into arterial strips. These results suggest that phencyclidine and (+)MK-801 have 2 separate actions on BMCA. They may constrict arterial rings by releasing TxA2 from cerebrovascular smooth muscle, and relax arterial rings by acting as calcium antagonists.

Delayed cognitive deficits can be alleviated by calcium antagonist nimodipine by downregulation of apoptosis following whole brain radiotherapy.

Radiation therapy is important for the comprehensive treatment of intracranial tumors. However, the molecular mechanisms underlying the pathogenesis of delayed cognitive dysfunction are not well-defined and effective treatments or prevention measures remain insufficient. In the present study, 60 adult male Wistar rats were randomly divided into three groups, which included a control, whole brain radiotherapy (WBRT) (single dose of 30 Gy of WBRT) and nimodipine (single dose of 30 Gy of WBRT followed by nimodipine injection intraperitoneally) groups. The rats were sacrificed 7 days or 3 months following irradiation. At 3 months, the Morris water maze test was used to assess spatial learning and memory function in rats. The results demonstrated that the WBRT group demonstrated a significantly impaired cognitive performance, decreased numbers of hippocampal Cornu Ammonis (CA)1 neurons and upregulated expression of caspase-3 in the dentate gyrus compared with those in the control and nimodipine groups. Reverse transcription-quantitative polymerase chain reaction analysis demonstrated that the WBRT group exhibited increased ratio of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax)/Bcl-2 compared with that in control and nimodipine groups on day 7 following irradiation. However, the WBRT group exhibited decreased levels of brain-derived neurotrophic factor (BDNF) compared with that in control and nimodipine groups at 3 months following brain irradiation. The levels of growth-associated protein 43 and amyloid precursor protein between the nimodipine group and WBRT group were not statistically significant. The present study demonstrated that neuron apoptosis may lead to delayed cognitive deficits in the hippocampus, in response to radiotherapy. The cognitive impairment may be alleviated in response to a calcium antagonist nimodipine. The molecular mechanisms involved in nimodipine-mediated protection against cognitive decline may involve the regulation of Bax/Bcl-2 and BDNF in the hippocampus.

Continuous intra-arterial nimodipine infusion in patients with severe refractory cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a feasibility study and outcome results.

Severe cerebral vasospasm is a major cause of death and disability in patients with aneurysmal subarachnoid hemorrhage. No causative treatment is yet available and hypertensive hypervolemic therapy (HHT) is often insufficient to avoid delayed cerebral ischemia and neurological deficits. We compared patients receiving continuous intra-arterial infusion of the calcium-antagonist nimodipine with a historical group treated with HHT and oral nimodipine alone. Between 0.5 and 1.2 mg/h of nimodipine were continuously administered by intra-arterial infusion via microcatheters either into the internal carotid or vertebral artery or both, depending on the areas of vasospasm. The effect was controlled via multimodal neuromonitoring and transcranial Doppler sonography. Outcome was determined by means of the Glasgow Outcome Scale at discharge and 6 months after the hemorrhage and compared to a historical control group. Twenty-one patients received 28 intra-arterial nimodipine infusions. Six months after discharge, the occurrence of cerebral infarctions was significantly lower (42.6 %) in the nimodipine group than in the control group (75.0 %). This result was reflected by a significantly higher proportion (76.0 %) of patients with good outcome in the nimodipine-treated group, when compared to 10.0 % good outcome in the control group. Median GOS was 4 in the nimodipine group and 2 in the control group (p = 0.001). Continuous intra-arterial nimodipine infusion is an effective treatment for patients with severe cerebral vasospasm who fail to respond to HHT and oral nimodipine alone. Key to the effective administration of continuous intra-arterial nimodipine is multimodal neuromonitoring and the individual adaptation of dosage and time of infusion for each patient.

Cerebral Vasospasm: A Review.

Cerebral vasospasm is a prolonged but reversible narrowing of cerebral arteries beginning days after subarachnoid hemorrhage. Progression to cerebral ischemia is tied mostly to vasospasm severity, and its pathogenesis lies in artery encasement by blood clot, although the complex interactions between hematoma and surrounding structures are not fully understood. The delayed onset of vasospasm provides a potential opportunity for its prevention. It is disappointing that recent randomized, controlled trials did not demonstrate that the endothelin antagonist clazosentan, the cholesterol-lowering agent simvastatin, and the vasodilator magnesium sulfate improve patient outcome. Minimizing ischemia by avoiding inadequate blood volume and pressure, administering the calcium antagonist nimodipine, and intervention with balloon angioplasty, when necessary, constitutes current best management. Over the past two decades, our ability to manage vasospasm has led to a significant decline in patient morbidity and mortality from vasospasm, yet it still remains an important determinant of outcome after aneurysm rupture.

Vasoplegic Syndrome after Oral Nimodipine Application in Patients with Subarachnoid Hemorrhage

Subarachnoid hemorrhage remains a serious disease with high mortality rate and often disastrous neurological outcome. After improvement of techniques to secure the underlying aneurysm leading to decrease of immediate complications such as rebleeding, cerebral vasospasm remains the major cause for mortality and morbidity after subarachnoid hemorrhage. The only FDA approved drug for treatment of cerebral vasospasm is the calcium antagonist Nimodipine that has shown beneficial effects on outcome. It is safe, cost efficient and the most widely studied drug for treatment of cerebral vasospasm. But it has reported side effects such as systemic hypotension, especially when used intravenously. The present paper reports about the occurence of severe systemic catecholamine refractory hypotension after oral application of the standard dosage of 60 mg nimodipine. In those patients we were only able to establish a sufficient arterial blood pressure after application of methylene blue suggesting that at least part of the underlying mechanism was NO related vasoplegia. Keeping in mind that vasoplegia can occur even after oral nimodipine application we suggest that there should be a test dosage of 15-30 mg nimodipine applied to evaluate the impact on each patient and avoid potential lethal hypotension.

Nerve growth factor and brain-derived neurotrophic factor but not granulocyte colony-stimulating factor, nimodipine and dizocilpine, require ATP for neuroprotective activity after oxygen–glucose deprivation of primary neurons

In previous work, we have demonstrated by radiolabeling, mass spectrometry and site-directed mutagenesis that nerve growth factor (NGF) as well as brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 2 (FGF2) are capable of ATP-binding and that this binding appears to be essential for their neuroprotective activity. In this study, we attempted to shed some light on the question whether ATP is a general prerequisite for neuroprotection. Therefore, we used the non-ATP-binding granulocyte colony-stimulating factor (GCSF), the calcium antagonist nimodipine and the NMDA antagonist dizocilpine to find out whether they need ATP for neuroprotection comparable to NGF and BDNF. However, ATP was not necessary for the neuroprotective effects of GCSF, nimodipine and dizocilpine on primary cultures of rat cortical neurons damaged by oxygen–glucose deprivation whereas neuroprotection was demonstrable for NGF and BDNF only when ATP was present in the culture medium at a concentration higher than ca. 0.4nmol/l. In circular dichroism studies ATP caused changes of the secondary structure of NGF but not of GCSF. Taken together, we suggest that ATP is not a general prerequisite for neuroprotectivity but some growth factors like NGF and BDNF can stimulate their receptors only if they have bound ATP.

EARLYDRAIN- outcome after early lumbar CSF-drainage in aneurysmal subarachnoid hemorrhage: study protocol for a randomized controlled trial

BackgroundAneurysmal subarachnoid hemorrhage (SAH) may be complicated by delayed cerebral ischemia, which is a major cause of unfavorable clinical outcome and death in SAH-patients. Delayed cerebral ischemia is presumably related to the development of vasospasm triggered by the presence of blood in the basal cisterns. To date, oral application of the calcium antagonist nimodipine is the only prophylactic treatment for vasospasm recognized under international guidelines.In retrospective trials lumbar drainage of cerebrospinal fluid has been shown to be a safe and feasible measure to remove the blood from the basal cisterns and decrease the incidence of delayed cerebral ischemia and vasospasm in the respective study populations. However, the efficacy of lumbar drainage has not been evaluated prospectively in a randomized controlled trial yet.Methods/DesignThis is a protocol for a 2-arm randomized controlled trial to compare an intervention group receiving early continuous lumbar CSF-drainage and standard neurointensive care to a control group receiving standard neurointensive care only. Adults suffering from a first aneurysmal subarachnoid hemorrhage whose aneurysm has been secured by means of coiling or clipping are eligible for trial participation. The effect of early CSF drainage (starting < 72 h after securing the aneurysm) will be measured in the following ways: the primary endpoint will be disability after 6 months, assessed by a blinded investigator during a personal visit or standardized telephone interview using the modified Rankin Scale. Secondary endpoints include mortality after 6 months, angiographic vasospasm, transcranial Doppler sonography (TCD) mean flow velocity in both middle cerebral arteries and rate of shunt insertion at 6 months after hospital discharge.DiscussionHere, we present the study design of a multicenter prospective randomized controlled trial to investigate whether early application of a lumbar drainage improves clinical outcome after aneurysmal subarachnoid hemorrhage.Trial registrationwww.clinicaltrials.gov Identifier: NCT01258257

The effect of the calcium antagonist nimodipine on the detoxification of soman in anaesthetized rabbits.

The effect of nimodipine, a vasoactive calcium antagonist, on the disappearance of soman from blood was studied in anaesthetized rabbits intoxicated with soman (10.8 micrograms kg-1 i.v.). Blood samples from the left heart ventricle and femoral artery were used to investigate soman detoxification. The concentrations of the soman isomers C+P- and C-P- in blood samples were determined by gas chromatography coupled with high-resolution mass spectrometry. During the sampling, 15-300 s after soman injection, the soman concentration in control animals decreased from 50 to 0.029 ng mL-1; in animals pre-treated with nimodipine (10 mg kg-1) it decreased from 15 to 0.033 ng mL-1. In animals pre-treated with nimodipine the soman concentration was significantly reduced during the first minute of sampling. No differences were detected between soman concentrations in samples from the heart and femoral artery. Acetylcholinesterase inhibition was also used as an indicator of soman activity; there was no difference between the activity of this enzyme in different peripheral organs of control and nimodipine-treated animals. Nimodipine reduces the initial concentration of soman in the blood, which might be of significance in the treatment of soman intoxication.

Nimodipine in aneurysmal subarachnoid hemorrhage: a randomized study of intravenous or peroral administration

The calcium antagonist nimodipine has been shown to reduce the incidence of ischemic complications following aneurysmal subarachnoid hemorrhage (SAH). Although most randomized studies have been focused on the effect of the peroral administration of nimodipine, intravenous infusion is an alternative and the preferred mode of treatment in many centers. It is unknown whether the route of administration is of any importance for the clinical efficacy of the drug. One hundred six patients with acute aneurysmal SAH were randomized to receive either peroral or intravenous nimodipine treatment. The patients were monitored for at least 10 days after bleeding in terms of delayed ischemic neurological deficits (DINDs) and with daily measurements of blood flow velocities in the middle cerebral arteries by using transcranial Doppler ultrasonography. Three months after SAH, clinical outcome and new cerebral infarctions according to MR imaging studies were recorded. Baseline characteristics (age, sex distribution, clinical status on admission, radiological findings, and aneurysm treatment) did not differ between the treatment groups. There was no significant difference in the incidence of DINDs (28 vs 30% in the peroral and intravenous groups, respectively) or middle cerebral artery blood flow velocities (> 120 cm/second, 50 vs 45%, respectively). Clinical outcome according to the Glasgow Outcome Scale was the same in both groups, and there was no difference in the number of patients with new infarctions on MR imaging. The results suggest that there is no clinically relevant difference in efficacy between peroral and intravenous administration of nimodipine in preventing DINDs or cerebral vasospasm following SAH.

Distinct effects of atypical 1,4‐dihydropyridines on 1‐methyl‐4‐phenylpyridinium‐induced toxicity

Our previous data obtained from in vivo experiments demonstrated high neuroprotective effects of three novel atypical neuronal non-calcium antagonistic 1,4-dihydropyridine (DHP) derivatives cerebrocrast, glutapyrone and tauropyrone. The present studies were carried out in vitro to clarify, at least in part, their mechanism of action in primary culture of cerebellar granule cells by use of 1-methyl-4-phenylpyridinium (MPP+) as a neurotoxic agent which causes dramatic oxidative stress. Cerebrocrast (highly lipophilic, with a classical two-ring structure) dose-dependently (0.01-10.0 microM, EC50 = 13 nM) reduced MPP+-induced cell death. At the same time, the calcium antagonist nimodipine (reference drug) protected cell death at much higher concentrations (EC50 = 12.4 microM). Cerebrocrast decreased also the generation of reactive oxygen species and loss of mitochondrial membrane potential. In contrast, low lipophilic amino acid-containing DHPs glutapyrone and tauropyrone (glutamate- and taurine-containing, correspondingly) were without significant effects indicating their distinct mode of action in comparison to cerebrocrast. We have demonstrated for the first time an ability of atypical non-calcium antagonistic DHP cerebrocrast (which has classical DHP structure elements and high lipophilicity) to protect MPP+-induced deterioration of mitochondrial bioenergetics. One may suggest mitochondria as an essential intracellular target for the neuroprotective action of cerebrocrast and indicate its usefulness in the treatment of Parkinson's disease.

Efficacy and Safety of Nimodipine in Subcortical Vascular Dementia

Evidence of drug efficacy in vascular dementia (VaD) is scanty. Therapeutic trials should address VaD subtypes. We studied the efficacy and safety of the calcium antagonist nimodipine in subcortical VaD. 242 patients defined as affected by subcortical VaD based on clinical (ICD-10) and computed tomography criteria were randomized to oral nimodipine 90 mg/d or placebo. 230 patients (121 nimodipine, mean age 75.2+/-6.1; 109 placebo, 75.4+/-6.0) were valid for the intention-to-treat analysis. At 52 weeks, the Sandoz Clinical Assessment Geriatric scale 5-point variation (primary outcome measure) did not differ significantly between the 2 groups. However, patients on nimodipine performed better than placebo patients in lexical production (P<0.01) and less frequently showed deterioration (3 or more point-drop versus baseline) on a Mini-Mental State Examination (28.1% versus 50.5%; chi2 P<0.01) and Global Deterioration Scale (P<0.05). Dropouts and adverse events were all significantly more common among placebo than nimodipine patients, particularly cardiovascular (30 versus 13; RR, 2.26; 95% CI, 1.11 to 4.60) and cerebrovascular events (28 versus 10; RR, 2.48; 95% CI, 1.23 to 4.98), and behavioral disturbances requiring intervention (22 versus 5; RR, 3.88; 95% CI, 1.49 to 10.12). A worst-rank analysis, performed to correct for the effect of the high dropout rate in the placebo group, showed additional significant differences in favor of nimodipine in Set Test and MMSE total scores. Nimodipine may be of some benefit in subcortical VaD. Confirming previous results, the safety analysis of this study shows that in this high-risk population, nimodipine might protect against cardiovascular comorbidities.

Intracranial aneurysm surgery and its future

The history of intracranial surgery for aneurysms is not a long one. The first direct operation on an intracranial aneurysm was performed by Norman Dott, who wrapped a ruptured aneurysm in 1933,1 and the first obliterative clipping of an aneurysm was performed by Walter Dandy in 1938.2 The results of surgery improved dramatically when the operating microscope was introduced in the 1960s3 and a subsequent improvement followed the use of the calcium antagonist nimodipine and the maintenance of a high fluid intake to lessen the risk of delayed cerebral ischaemia.4 For many years clipping of a ruptured aneurysm was regarded as the definitive mode of treatment, but the development of the GDC coil in 1990 allowed an alternative approach that avoided the hazards of open surgery. In the latter half of the 1990s, as experience of endovascular techniques spread, this form of treatment began to displace open surgery and the International Subarachnoid Aneurysm Trial (ISAT) was set up to compare the efficacy of the two forms of treatment. Early in 2002 the trial was interrupted by the steering committee when an intermediate analysis of the results revealed that, in the short term at any rate, the results of endovascular coiling were superior to those of clipping, in that the chances of survival free of disability at one year were significantly better for coiling. Furthermore, the risk of rebleeding from a successfully coiled aneurysm at one year was only 0.16%.5 Although this still leaves open the long-term risks of aneurysm re-formation and rebleeding after coiling (a risk which is negligible after successful clipping), we believe that the results of ISAT must spell the end of aneurysm surgery—though no doubt there will be a transitional period of some years before surgery finally disappears. As things stand, it is difficult to advise surgery in those cases where coiling is practicable, and publication of the ISAT probably led to an immediate shift towards coiling in most units in the UK. The current margin in favour of endovascular treatment is likely to increase in the future, for the following reasons. Endovascular as opposed to surgical treatment is an evolving technique. Not only is the microtechnology constantly improving but also more and more neuroradiologists are acquiring and honing their skills in this field. As this happens, increasing proportions of aneurysms are proving amenable to endovascular treatment. By contrast, the technology of surgery has been static for many years and, after the quantum leap in results provided by the introduction of the operating microscope and associated microinstrumentation, it is difficult to see how the techniques of open surgery could be further improved. Furthermore, as the use of endovascular techniques extends, so the surgical expertise will be lost. Already the pool of very experienced surgeons is draining away as a result of death and retirement, and as these surgeons disappear the advantages of endovascular treatment will become greater still. The number of cases unsuitable for endovascular treatment will shrink to the point where there will be a residue of difficult and complex cases for which only surgery is available. However, it is by no means certain that surgery would be justified in such cases. These are likely to be patients with, for example, giant and complex aneurysms in inaccessible situations where even at present surgical as opposed to conservative treatment may be difficult to justify. This will be still more true when the surgical skills honed upon hundreds of more straightforward cases have been lost. For these reasons, any review of aneurysm surgery must be largely of historical interest. However, we think it of value to touch on some topics that have concerned the senior author in the course of 30 years of aneurysm surgery during which time he has treated almost a thousand cases. Over this period he had prepared prospective datasheets for every patient treated under his care. These datasheets have provided much information on the clinical course of the patients treated, the technical difficulties encountered at surgery and the postoperative problems that arose.

Nimodipine Affects the Microcirculation and Modulates the Vascular Effects of Acetylcholinesterase Inhibition

The present investigation was undertaken in order to study whether microvascular effects of the calcium antagonist nimodipine induces changes that can explain an increased detoxification of the highly toxic cholinesterase inhibitor soman. Anaesthetised, tracheotomised and artificially ventilated rats were treated intra-peritoneally (ip) with nimodipine, 10 mg kg-1 or vehicle followed one hour later by the exposure to 45 μg kg-1 soman (iv). Nimodipine per se induced a vasodilation in the intestine, myocardium and other muscles. In the abdominal skin soman elicited a significant vasoconstriction that was turned into an increased blood flow after nimodipine pre-treatment. A slight vasoconstriction in diaphragm of soman intoxicated rats was turned into a significant vasodilation by nimodipine pre-treatment. In the intestinal parts no effect of soman was detected. However, in nimodipine pretreated animals soman induced a significant vasoconstriction. The capacity of soman detoxifying processes, i.e. enzymatic hydrolysis and covalent binding to different esterases, is unequally distributed throughout the body.Together with the knowledge of the detoxifying processes of cholinesterase inhibition the results support our theory, that nimodipine alters the peripheral blood flow in a beneficial way resulting in improved detoxification ability.

The effects of dantrolene alone or in combination with nimodipine in glutamate-induced neurotoxicity in cerebellar granular cell cultures of rat pups

Despite the existence of some positive and negative reports on dantrolene in ischemic states, combined application of an endoplasmic reticulum Ca2+release inhibitor and a calcium channel blocker has not yet been elucidated. In the present study, we have investigated the role of dantrolene in subsequent doses alone or in coexistence with the dihydropyridine calcium antagonist nimodipine (10−4M concentration) in glutamate-induced (10−7M) neurotoxicity in cerebellar granular cell cultures of rat pups. Glutamate induced neuronal cell death at a concentration of 10−7M. Despite the fact that none of the groups tested were able to reverse cell death to control values, dantrolene was found to be effective in preventing glutamate toxicity in cerebellar cultures of rat pups. The protective effect of dantrolene potentialized in combination with nimodipine at all doses tested. The most effective dose of dantrolene was found to be 10−4M in combination with nimodipine. As a result, both extracellular and internal calcium stores play important roles in the genesis of neuronal cell death induced by glutamate.

Antiischemic therapy of severe prolonged vasospasm after aneurysmal SAH: effects on quality of life.

The in-between broad acceptance of early surgery and improved intensive care management have led to a significant reduction of vasospasm associated morbidity and mortality within the last 25 years. However, the large body of publications concerned with the prevention and treatment of vasospasm still denote its role as one of the major complications in the postoperative management after aneurysmal subarachnoid hemorrhage (SAH). Next to purely mechanical measures such as balloon dilatation of vasospastic vessels and intraarterial papaverine infusion, which as of now lack verification by means of larger controlled clinical trials, established medical treatment concepts focus on pharmacological approaches such as the calcium antagonist nimodipine and hypervolemic hemodilution and hypertension (“Triple-H” therapy).KeywordsSAHvasospasmtriple-H therapyquality of life

Cardiac bypass haemostasis: putting blood through the mill.

Cardiac bypass haemostasis: putting blood through the mill.

Excitotoxicity and neuroprotection

Glutamate, the most widely used excitatory amino acid transmitter in the brain, stimulates ionotropic and metabotropic receptors. There is an increased release of glutamate after cerebral ischemia or hypoxia which could cause overstimulation of its receptors leading to an increase in the intracellular Ca 2+ concentration ([Ca 2+] i). Sustained elevation in [Ca 2+] i is assumed to set various pathological processes into motion which could degenerate neurons by activating proteases, lipases, endonucleases and nitric oxide synthases and by promoting the formation of free oxygen radicals. Drugs capable of inhibiting the increase in [Ca 2+] i such as calcium antagonists, NMDA and AMPA antagonists protect neurons against damage. To prevent Ca 2+ influx into neurons most efficaciously NMDA-operated and voltage-sensitive Ca 2+ channels were simultaneously blocked. Both the NMDA antagonist dizocilpine (MK-801) and the calcium antagonist nimodipine were added to glutamate-treated cultures of rat hippocampal neurons and these two drugs caused an overadditive neuroprotective effect. NMDA receptor stimulation leads to an augmented formation of NO and free oxygen radicals and that is the reason why radical scavengers are effective in protecting neurons against glutamate-induced damage. Furthermore, TGF-β1, the lesion form of the TGF-β family which is discussed to stabilize the cellular Ca 2+ homeostasis and to reduce free radical formation also protects neurons against excitotoxic damage. It is suggested that an increased [Ca 2+] i is significantly involved in neuronal damage and the inhibition of the increase in [Ca 2+] i protects neurons against damage.

Review on traumatic subarachnoid hemorrhage

Recent studies demonstrated clinical significance of the presence of traumatic subarachnoid hemorrhage (tSAH) on the initial CT-scan after head injury. Investigations show similarities between traumatic and a!1eurysmal SAH suggesting that a similar therapeutic approach as used in spontaneous SAH patients might be beneficial in tSAH patients. Evidence of the clinical significance of the finding of tSAH on CT after head injury and the beneficial use of the calcium antagonist nimodipine in tSAH patients are reported. [Neural Res 1997; 19: 230-232]

Current Management of Aneurysmal Subarachnoid Hemorrhage Guidelines from the Canadian Neurosurgical Society

Published medical evidence pertaining to the management of aneurysmal subarachnoid hemorrhage (SAH) was critically reviewed in order to prepare practice guidelines for this condition. SAH should be considered as a possible cause of all sudden and/or unusual headaches, and every attempt should be made to recognize mild SAHs, as they are still frequently misdiagnosed. The first test for SAH is computed tomography (CT), followed by lumbar puncture when the CT is negative for intracranial bleeding (the case in only several per cent of patients within 24 hours of aneurysm bleeding). Urgent cerebral angiography is necessary to detect the underlying cerebral aneurysm. The advantage of rapid diagnosis of SAH followed by early aneurysm repair is minimizing the risk of catastrophic aneurysm rebleeding. Early surgery for aneurysm repair is often possible and is recommended, unless the aneurysm location or size renders it technically difficult to expose in clot-laden subarachnoid cisterns beneath an acutely swollen brain. Aneurysm ablation is optimally accomplished with open microsurgery and clipping of the aneurysm neck, although other options include proximal parent artery occlusion, "trapping" of the aneurysmal segment of the artery, and embolization of thrombogenic materials (e.g., platinum "microcoils") directly into the aneurysm dome using endovascular techniques. Neurological outcome following SAH is also optimized through the prevention of secondary SAH complications, and further management specific for ruptured cerebral aneurysms can include anticonvulsants, neuroprotectants, and various agents and techniques to prevent or reverse delayed-onset cerebral vasospasm. All patients with aneurysmal SAH should be treated with the calcium antagonist nimodipine, and in certain circumstances patients should receive anticonvulsants. Induced arterial hypertension, hypervolemia and in some instances percutaneous balloon angioplasty are recommended to reverse vasospasm causing symptomatic cerebral ischemia prior to cerebral infarction.