Action Of Flunarizine Research Articles

Cortical-spreading depression: at the razor’s edge of scientific logic

For over 60 years, cortical spreading depression (CSD) has mesmerized neurologists immersed in headache research. While science and logic are (or, at least, should be) inseparable, CSD—a largely experimental physiological reality—has dissociated the two in headache-related research. Although the need for a fresh pathophysiologic approach to migraine and other primary headaches unrelated to the neuronal (neural) or vascular theories has been voiced two decades ago [1, 2], and the issue has been questioned again recently [3, 4], the fascination for CSD as the basis for migraine remains largely undimmed. Currently, the pathogenetic role of CSD in migraine is widely accepted as an immutable fact or truth, and, any challenge to its role is regarded as almost heretical. In this issue of TJHP, Yu and colleagues present an interesting facet of the mechanism of action of flunarizine in a rat model of CSD. The key finding is that flunarizine can alleviate cerebral mitochondrial injury under both normal and hypoxic conditions, a not unexpected effect attributed likely to blockade of voltage-gated calcium channels. However, hypoxia attenuated the protective effect of flunarizine on the CSD amplitude. In a nutshell, CSD leads to oxidative stress, or aggravated hypoxic conditions in the brain, and, these changes can be attenuated by flunarizine. In extrapolating these experimental results in rats to humans, and, in particular, to migraine pathophysiology, certain features need careful consideration. The role of flunarizine in migraine therapeutics is itself uncertain. While flunarizine is used (albeit, with low-grade evidence) for migraine prophylaxis in several countries, it has yet to be approved for this indication by the United States Food and Drug Administration. Whereas the US FDA looks for evidences from randomized clinical trials (RCT) to stamp its approval of drugs such as flunarizine, the RCT itself is not without flaws, and, its utility in migraine is limited by the very nature of the disorder [5]. At a more fundamental level, flunarizine is a potent vasodilator of the cerebral vessels. Alcohol and nitroglycerin are well-established vasodilators that precipitate migraine predictably without any known effect(s) on CSD. There is, however, a significant clinical difference between sustained prophylactic cerebral vasodilatation (flunarizine) and relatively sudden cerebral vasodilatation (alcohol, nitroglycerin). Nevertheless, evidence that flunarizine can provide extended, satisfactory prophylaxis for most migraine patients is conspicuously sparse. The limitations of CSD as a pathogenetic model for human neurological illnesses, particularly migraine, have been discussed almost exhaustively; additionally, a large and growing body of evidence indicates that CSD is biologically adaptive or neuroprotective [4]. There is not a single description of homonymously distributed migrainous scintillating scotoma; the scotoma has always been described as spreading towards the temporal field, right or left. Even Lashley [6] did not describe spread of his own migrainous scotoma towards the nasal field. As a neuropathologic concept, CSD has spawned much confusion and speculation, and, has outlived its usefulness. The time is, perhaps, ripe to bid farewell to an enduring and revered notion in neurology. Only then, we might step out of the maze of clinical and therapeutic assumptions that sustain a prominent role for CSD in human neuropathology. Such comprehension would also mark the beginning of the end of the stalemate that has gripped migraine research for over half a century.

Flunarizine blocks voltage-gated Na+ and Ca2+ currents in cultured rat cortical neurons: A possible locus of action in the prevention of migraine

Although flunarizine (FLN) has been widely used for migraine prophylaxis with clear success, the mechanisms of its actions in migraine prophylaxis are not completely understood. It has been hypothesized that migraine is a channelopathy, and abnormal activities of voltage-gated Na+ and Ca2+ channels might represent a potential mechanism of cortical hyperexcitability predisposing to migraine. The aim of the present study was to investigate the effects of FLN on Na+ and Ca2+ channels of cultured rat cortical neurons. Sodium currents (INa) and calcium currents (ICa) in cultured rat cortical neurons were monitored using whole-cell patch-clamp recordings. Both INa and ICa were blocked by FLN in a concentration-dependent manner with IC50 values of 0.94μM and 1.77μM, respectively. The blockade of INa was more powerful at more depolarizing holding potentials. The steady-state inactivation curve of INa was shifted towards more hyperpolarizing potentials by FLN. FLN significantly delayed the recovery from fast inactivation of INa. Furthermore, the action of FLN in blocking INa was enhanced at higher rates of channel activation. Blockades of these currents might help explain the mechanism underlying the preventive effect of FLN on migraine attacks.

Effects of flunarizine on spontaneous synaptic currents in rat neocortex.

Flunarizine, a non-selective blocker of voltage-dependent Ca(2+) and Na(+) channels, is clinically effective against several neurological disorders, including epilepsy, migraine, and alternating hemiplegia of childhood. We examined the effects of flunarizine on spontaneous post-synaptic currents in acute brain slices maintained in vitro using patch-clamp electrophysiology. Flunarizine significantly attenuated the amplitude of spontaneous currents in pyramidal neurons from juvenile rat neocortex. Flunarizine had no effect on miniature spontaneous events recorded in the presence of tetrodotoxin, a blocker of voltage-dependent sodium channels. In high (9 mM) extracellular potassium, flunarizine reduced the amplitude and frequency of the spontaneous currents. Additionally, dimethyl sulfoxide, the solvent used in our experiments, reduced the amplitude of spontaneous currents, but only in high extracellular potassium. Our data suggest that the clinical activity of flunarizine may in part be a consequence of reducing spontaneous synaptic currents in the neocortex, especially under conditions of heightened neuronal activity.

Ocular hypotensive action of topical flunarizine in the rabbit: role of sigma 1 recognition sites.

In a previous study we ascertained the presence of sigma1 and sigma2 recognition sites in the rabbit iris-ciliary body, an ocular structure involved in aqueous humor production and drainage. We characterized the sigma1 sites using the preferential ligand (+)-pentazocine, which caused a significant reduction of intraocular pressure (IOP). In the present study, flunarizine, a calcium channel blocker with a complex pharmacological profile, bound to sigma1 sites expressed in the iris-ciliary body with moderate affinity (K(i) = 68 nM). Unilateral topical flunarizine (0.01-0.1%) caused a dose-related reduction of IOP in ocular normotensive rabbits and in the alpha-chymotrypsin model of ocular hypertension, without altering the IOP of the contralateral eye. This activity was blocked by the sigma1 site antagonist NE-100 [N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine HCl] which, by itself, had no effect on IOP. Detection of flunarizine in rabbit iris-ciliary body homogenates, after topical instillation, showed that it adequately penetrates the rabbit eye. To investigate mechanisms that may contribute to ocular hypotension induced by sigma1 agonists, we carried out in vitro studies on the isolated rabbit iris-ciliary body. Flunarizine (IC50 = 5. 96 nM) and (+)-pentazocine (IC50 = 3. 81 nM) inhibited [3H]norepinephrine release. Moreover, flunarizine (IC50 = 6.34 nM) and (+)-pentazocine (IC50 = 27.26 nM) also antagonized isoproterenol-induced cAMP accumulation. The action of flunarizine and (+)-pentazocine was sensitive to NE-100 antagonism; however, this latter compound partially prevented their effect on [3H]norepinephrine and cAMP accumulation. These findings indicate that flunarizine and (+)-pentazocine interact with ocular sigma1 sites and may prove effective in the control of ocular hypertension.

Prolactin response to bromocriptine in flunarizine-treated migrainous women.

Flunarizine, a calcium channel blocker, is widely used in migraine prophylaxis. Although an antidopaminergic effect has been suggested for this drug, it is unclear whether the antimigraine action of flunarizine involves the dopaminergic system. We studied the inhibitory response of prolactin to acute administration of bromocriptine, a D2 dopamine receptor agonist, before and after 1 month of treatment with flunarizine in migrainous women. Flunarizine treatment increased basal prolactin levels, but it did not reduce the inhibitory response of prolactin to acute bromocriptine administration. These findings do not support the hypothesis that flunarizine acts as a direct antagonist at the D2 dopamine receptor.

Flunarizine inhibits a high-threshold inactivating calcium channel (N-type) in isolated hippocampal neurons

The action of flunarizine on the high-threshold inactivating calcium channel (N-type) in hippocampal neurons of the rat was investigated using the whole-cell voltage clamp technique. Flunarizine reduced the currents at all test potentials, without shifting the peak of the current-voltage relationship along the voltage-axis. The drug did not affect the activation curve, but drastically decreased the slope conductance in the linear region of the current-voltage relationship. Block of the current by flunarizine occurred in a use-dependent way. Flunarizine was without effect when applied intracellulary, and the onset of action, when applied extracellularly, was slow (range of minutes). The Kd for the block by flunarizine obtained after 6 repetitive depolarizations at 0.2 Hz (pulse duration 150 ms) from -90 mV to 0 mV was 0.8 microM. In conclusion, we present electrophysiological evidence that flunarizine blocks the high-threshold inactivating Ca channel of hippocampal neurons of the rat. We discuss the possibility that flunarizine might inhibit neuronal transmitter release by means of this effect.

Investigations of the antifibrillatory activity of flunarizine and lidoflazine in isolated hearts of rabbits and guinea pigs

In Langendorff-perfused rabbit hearts, ventricular fibrillation threshold (VFT) was measured by applying rectangular impulses of 3ms duration at a frequency of 20Hz. Perfusion with 0.2 and 0.4 microM of flunarizine or 0.2 microM of lidoflazine produced a significant rise in VFT. When the hearts were perfused with higher concentrations of either drug (0.8 microM flunarizine, 0.4 and 0.8 microM lidoflazine), VFT did not continue to increase in a dose-dependent manner but rather a smaller increase in VFT than the previous dose was observed. Both drugs caused significant decrease in the spontaneous heart rate and amplitude of contraction of the isolated rabbit heart. In the Langendorff-perfused guinea pig heart, perfusion with 0.8 microM of flunarizine produced complete protection against ouabain-induced ventricular fibrillation while 7 out of 7 and 1 out of 6 hearts fibrillated in the presence of 0.2 and 0.4 microM of the drug respectively. During perfusion with 0.2, 0.4 and 0.8 microM of lidoflazine the incidence of ventricular fibrillation was 3 out of 6, and 5 out of 7 hearts respectively. These results may indicate a limited effectiveness of these 2 calcium entry blockers against ventricular fibrillation.

Pharmacological basis and therapeutic efficacy of flunarizine in peripheral artery disease.

In the last few years we have accumulated some evidence that calcium entry blockers could interfere with an endogenous purinergic mechanism, namely, with membrane adenosine receptors.’” This property seemed to be shared by different groups of such drugs, independently from their chemical structure, thus opening new questions on the molecular mechanism of action.24 Among these substances, first flunarizine and then dihydropyridines claimed our attention, and now we want to summarize the findings of our studies, not following the logical development of the adenosine hypothesis in our mind, but assembling our data according to the type of experimental design. In this paper the thread of the argument implies a continuous hypothetical comparison with the adenosine system. Our studies dealt with clinical pharmacological investigations on the circulatory activity of flunarizine either in control subjects or in peripheral obliterative arterial disease (POAD) patients. The design of the study included the plethysmographic investigation of the leg hemodynamics after flunarizine infusion and after treatment with drugs that either block adenosine receptors, such as theophylline, or inhibit adenosine uptake, such as dipyridamole. Finally a cellular model was approached to clarify a possible interference of calcium entry blocker with adenosine a t the membrane receptor level.

Evaluation of Flunarizine in Patients with Meniere's Disease

In an open multicentre pilot study, 32 patients affected with Meniere's disease were treated with the cerebrally effective calcium antagonist flunarizine for 12 weeks. By means of the so-called vestibular index, the therapeutic results could be documented in a rapid and clear manner; the vestibular index takes into account both the subjective statements of the patients and objective pathological vestibular findings in terms of figures. The mean value of this vestibular index of 32 patients with Meniere's disease was 9.5 before treatment and only 4.0 at the end of the therapy, which is indicative of a positive therapeutic effect. In the final evaluation, the action of flunarizine was generally considered very beneficial both by the attending physicians and the patients.

Protective effect of flunarizine against cerebral hypoxia-anoxia in mice and rats.

The protective effect of flunarizine against cerebral hypoxia-anoxia was investigated with various experimental models in mice and rats. The effect of flunarizine was compared with those of cinnarizine, verapamil and pentobarbital. The oral treatment of animals with flunarizine resulted in a consistent and long-lasting-protection against cerebral hypoxia-anoxia in all the models examined: Cytotoxic anoxia by KCN injection, hypercapnic anoxia induced by stopping artificial respiration, hypobaric hypoxia and normobaric hypoxia. The minimal effective dose of flunarizine was 1 to 20 mg/kg. The activity of flunarizine was 4 to 30 times as potent as that of cinnarizine and pentobarbital. Verapamil showed little or no protective effect. The mode of action of flunarizine was different from that of pentobarbital, which showed protection at anaesthetizing doses. These results indicate that flunarizine possesses a universal protective effect against cerebral hypoxia-anoxia, through the mechanism involved remains to be clarified. Hence, it is suggested that flunarizine might exert a beneficial effect on oxygen insufficiency of the brain resulting from cerebral ischemia.

Selective Abolition Of Ca-Dependent Responses Of Smooth And Cardiac Muscles By Flunarizine

The inhibitory effect of flunarizine on the Ca-dependent responses was compared with that of verapamil in isolated smooth and cardiac muscles. Flunarizine at a small dose shifted to the right the dose-response curve for Ca2+ of the phasic contraction due to electric stimuli in rabbit basilar strips, while in a large dose, flunarizine reduced the maximum tension and slope of the dose-response curve. The high K+-induced vasoconstriction of the rabbit basilar artery was inhibited by flunarizine. However, the action of flunarizine was about 30 times slower than findings with verapamil. The spontaneous activity of the rat portal vein was less susceptible to flunarizine, whereas that of rat uterus was completely inhibited by flunarizine. Flunarizine possessed moderate negative chronotropic and inotropic actions on the right atria and papillary muscles of the rabbit. Our experiments indicate that flunarizine is selective in antagonizing Ca-dependent contraction of the rabbit basilar artery, probably by blockade of the transmembrane Ca. It is also possible that the slow onset of action and nonsurmountable antagonism produced by flunarizine is due to other pharmacological interventions such as delayed effect of metabolites, stabilizing action or tight binding on the cell membrane of vascular smooth muscles.

Flunarizine and Cinnarizine as Vestibular Depressants

The authors analysed the vestibular depressant activity of flunarizine and cinnarizine, as compared to a placebo, in 58 patients with peripheral labyrinthine disorders. The activity of the medications was judged by the reduction of the average velocity of the slow phase of the post-caloric nystagmus, before and after treatment. In spite of being administered in a smaller dosis, flunarizine appeared to have a more intense vestibular supressant activity, as judged by different statistical tests.