Acute and chronic triptan exposure neither alters rodent cerebral blood flow nor worsens ischemic brain injury.

Although it is still debated whether vasoconstriction underlies migraine resolution by triptans, they are not recommended in patients at cardiovascular risk. However, relationship between stroke incidence and triptan use is unclear, and it is unknown whether acute or chronic use of these drugs worsens ischemic brain injury. To address this issue, we investigated the effect of clinically-relevant doses of the potent cerebral artery vasoconstrictor eletriptan on cerebral blood flow (CBF) and brain infarct volumes, as well as on expression of genes involved in cerebrovascular regulation. We report that acute treatment of rats or mice with eletriptan did not reduce basal CBF, which promptly dropped upon treatment with prazosin or dihydroergotamine. Acute of chronic (1month) eletriptan also did not affect CBF changes and infarct volumes in mice undergoing brain ischemia/reperfusion. Finally, chronic eletriptan reduced brain mRNAs for PACAP and VIP, leaving unaffected those for 5HT1B/DR and CGRP. No significant transcript changes were found in dura mater. Data suggest that the impact of triptans on cerebral hemodynamic should be re-evaluated, as well as their propensity to increase stroke risk in migraineurs.

New therapeutic developments in chronic migraine.

PURPOSE OF REVIEW: Chronic migraine is a common cause of chronic daily headache, which is often refractory to standard treatment. New research has increased our understanding of this disorder and its treatment. This review focuses on recent clinical trials and advances in our understanding of migraine pathophysiology. RECENT FINDINGS: Migraine research has traditionally focused on the more common episodic form of the disorder, but recent clinical trials have started to focus on chronic migraine or chronic daily headache. Topiramate, onabotulinum toxin type A, gabapentin, petasites and tizanidine are among the agents that appear to be effective in the treatment of chronic migraine. New acute medications including an inhaled form of dihydroergotamine will soon be available and neuromodulatory procedures such as occipital nerve stimulation may be effective for the most disabled patients. In the past few years, other studies have shed light on potential risk factors for chronic migraine such as medication-overuse headache, temporomandibular disorders, obstructive sleep apnea and obesity. SUMMARY: This review explains advances in the treatment of chronic migraine, a common disorder seen in neurological practice. These new advances in preventive treatment and a better understanding of its risk factors will allow clinicians to better identify individuals at greatest risk and prevent the development of chronic migraine.

Cardiovascular excitatory effect on rats of a fraction isolated from the eyestalk of shrimp: Peneaus vanameii.

The crustacean nervous system is an important source of substances with diverse biological activities, particularly affecting invertebrate cardiocirculatory physiology. However, the effects of these substances on the cardiovascular system of higher vertebrates are not very well documented. The purpose of this study was to evaluate the effects of a cardioexcitatory substance (CES) isolated from the eyestalk of the shrimp Peneaus vanameii on rat cardiovascular function. The administration of a purified fraction of this substance raised mean arterial pressure by 37.33 +/- 5.00 mm Hg, pulse pressure 35.00 +/- 4.93 mm Hg and heart rate 80.00 +/- 12.83 beats/min over basal values (p < 0.01). Evaluation of the possible underlying mechanisms of this hypertensive and tachycardic effect reveled that dihydroergotamine pretreatment (20 microg/0.2 mL) reduced the effect of CES on mean blood pressure, but not on heart rate. Propranolol pretreatment (4 microg/0.2 mL) reduced the tachycardia, but not the hypertensive response. Enalapril pretreatment (5 microg/0.2 mL) did not modify the effects induced by CES on heart rate or blood pressure, and the verapamil pretreatment (1 microg/0.2 mL) reduced both cardiovascular changes by 85% (p < 0.01). These results indicate that CES isolated from the shrimp eyestalk produces hypertension and tachycardia mediated by adrenergic receptors in association to calcium channels activation.

Evaluation of the anti-emetic potential of anti-migraine drugs to prevent resiniferatoxin-induced emesis in Suncus murinus (house musk shrew).

Activation of vanilloid receptors has commonly been used to facilitate neurogenic inflammation and plasma exudation to model components of the pathogenesis of migraine; however, these studies have been performed mainly in species lacking the emetic reflex. In the present studies, therefore, we used Suncus murinus, a species of insectivore capable of emesis, to investigate if the vanilloid receptor agonist resiniferatoxin is capable of modeling the emesis associated with migraine. Resiniferatoxin (100 nmol/kg, s.c.) induced an emetic response that was antagonized significantly (P<0.05) by ruthenium red (1-3 micromol), (2R-trans)-4-[1-[3,5-bis(trifluromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-hydroxybutanedioate (R116301; 10-100 micromol/kg), and scopolamine (1 micromol/kg), but not by dihydroergotamine (0.3-3 micromol/kg), sumatriptan (1-10 micromol/kg), methysergide (1-10 micromol/kg), tropanyl 3,5-dichlorobenzoate (MDL72222; 3-30 micromol/kg), ondansetron (0.3-3 micromol/kg), metoclopramide (3-30 micromol/kg), domperidone (3-30 micromol/kg), diphenhydramine (1-10 micromol/kg), or indomethacin (3-30 micromol/kg). The failure of a wide range of representative anti-migraine drugs to reduce retching and vomiting limits the use of this model to identify/investigate novel treatments for the emesis (and nausea) associated with migraine attacks in humans. However, the results provide further evidence for the involvement of a novel vanilloid receptor in resiniferatoxin-induced emesis and implicate both tachykinins and acetylcholine in the pathway(s) activated by resiniferatoxin in S. murinus.

[Significance of sympathetic-adrenal structures in hematopoiesis regulation in cytostatic myelodepression]. / Znachenie simpatiko-adrenalovykh struktur reguliatsii gemopoéza pri tsitostaticheskoi mielodepressii.

The role of the sympathetic nervous system in the regulation of bone marrow hematopoiesis has been studied on mice CBA after administration of 5-fluorouracil (114 mg/kg). The double injection (3-5 minutes before and 5 hours after 5 + U) of ganglionic blocking drug (pentamine, 6 mg/kg), alpha-adrenergic (dihydroergotamine, 3.9 mg/kg) or beta-adrenergic antagonists (propranolol, 5 mg/kg) inhibited the post-cytostatic reparation of erythro- and granulocytopoiesis. Besides, addition of the same neurotropic antagonists and 5-FU (10(-7) M) to bone marrow culture led to 1.5-3 fold decrease of cell content in comparison with alone cytostatic after 24 hours incubation. On the contrary injection of neuroblocking agents (twice in 5 hours) on day 3 after 5-FU administration elevated the total count of erythroid cells immature and mature granulocytic leukocytes in bone marrow and polymorphonuclear leukocytes in blood. Thus, the unequal role of the sympathetic nervous system in the regulation of hematopoiesis at the different periods after high dose of 5-FU administration has been demonstrated.

The effect of some drugs with purported antianoxic effect on veratridine-induced purine release from isolated rat hypothalamic synaptosomes.

Several drugs claimed to protect against anoxic damage to the brain and/or to aleviate symptoms of senility were tested for their ability to influence purine overflow from hypothalamic synaptosomes. Theophylline did not influence the total purine release but tended to decrease the nucleoside and increase the nucleotide release. Cyclic nucleotide phosphodiesterase inhibitors were ineffective, whereas drugs that inhibit carrier mediated nucleoside transport inhibited veratridine-induced purine release. Some ergot derivatives, some vinca-analogues and the vasodilator ifenprodil also decreased stimulated purine release, but their effect could not be attributed to adenosine transport inhibition. The results suggest that drugs are reported to aleviate symptoms of anoxic damage or senility may inhibit the release of adenosine and related compounds in the central nervous system. Some possible reasons why a decreased purine release may protect against ischaemic brain damage are discussed.

The vasopressor and oxytocic activities of the hypothalamus and neurohypophysis are influenced by inhibited alpha-adrenergic transmission during dehydration and subsequent rehydration in the white rat.

During equilibrated water metabolism a single dose of dihydroergotamine (DHE) increased vasopressin release from the neurohypophysis; it had no effect on oxytocin content in the hypothalamus and neurohypophysis. After two days of dehydration DHE somewhat restrained the decrease of oxytocin in the hypothalamus; the release of vasopressin from the neurohypophysis was then increased. Under severe dehydration, i.e. under conditions of potent osmoreceptor stimulation, DHE influenced the vasopressin content neither in the hypothalamus nor in the neurohypophysis, but in some way it intensified oxytocin depletion in the neurohypophysis. Following two days of rehydration DHE somewhat restrained the renewal of vasopressin in the hypothalamus. No changes of oxytocin in the hypothalamus could be demonstrated at that time; in the neurohypophysis DHE intensified vasopressin repletion, but inhibited oxytocin repletion. Following four and eight days of rehydration DHE had no influence on vasopressin repletion rate in the hypothalamus and neurohypophysis. At that time oxytocin repletion in the neurohypophysis was increased; in the hypothalamus it was not affected by DHE. It is concluded that the response of the hypothalamo-neurohypophyseal system to alpha-adrenergic blockade-as brought about by dihydroergotamine treatment-seems to be dependent on the actual state of water metabolism. Impulses from the osmoreceptors may be therefore of some important in modifying the change in vasopressin and oxytocin release resulting from inhibition of alpha-adrenergic transmission through neural chains including units susceptible to dihydroergotamine.

Effects of acute and subacute treatment with ergot drugs on the GABA system in specific brain regions.

The effect of dihydroergotoxine and dihydroergotamine on gamma-aminobutyric acid (GABA) levels, the aminooxyacetic acid (AOAA)-induced accumulation of GABA, and the in vitro activity of L-glutamate decarboxylase (GAD) have been examined in various regions of rat brain. Dihydroergotoxine (1 mg kg-1) decreased the concentration of GABA and enhanced the AOAA-induced accumulation of GABA in the caudate nucleus and cingulate cortex. Dihydroergotoxine 10.0 mg kg-1 decreased the AOAA-induced accumulation of GABA in the substantia nigra. The repeated treatment with dihydroergotoxine, 0.05 mg kg-1 for eight days, also decreased the concentration of GABA in the cingulate cortex and diminished the AOAA-induced accumulation of GABA in the substantia nigra. The administration of 0.1 mg kg-1, but not higher doses; of dihydroergotamine, enhanced the AOAA-induced accumulation of GABA in the cingulate cortex. Dihydroergotamine (10.0 mg kg-1) decreased the concentration of GABA in the cingulate cortex and increased the AOAA-induced accumulation of GABA in the caudate nucleus. The activity of GAD in the cingulate cortex, but not in the caudate nucleus, was enhanced after a high dose of dihydroergotamine. Observed increases in the AOAA-induced accumulation of GABA indicate that dihydroergotoxine and dihydroergotamine in at least some brain areas cause an apparent increase in GABA synthesis in vivo, which is presumably a compensatory phenomenon due to a diminished GABAergic transmission under the influence of these drugs.

[Pharmacologic analysis of monoaminergic mechanisms of the medial hypothalamus in food-getting conditioned reflexes in rats]. / Farmakologicheskii analiz monoaminergicheskikh mekhanizmov medial'nogo gipotalamusa v pishchedobyvatel'nykh uslovnykh refleksakh u krys.

In the study of food-procuring conditioned reflex in rats it was found that microinjection of noradrenaline and dopamine in the medial hypothalamus impedes its realization, prolonging the reflex latency, lowering its value and the number of conditioned food-procuring movements. The effects of catecholamines on food-procuring conditioned activity are specific and effectuated correspondingly via alpha-adrenoreceptors or receptors of the hypothalamic neurones sensitive to haloperidol and aminazine. Local administration of GABA to the hypothalamus prolongs the latency of the food-procuring conditioned reflex, but does not change its value and the number of conditioned food-procuring movements. The effect of GABA is not due to the effect on adreno- and dopamine receptors of the hypothalamus.

Dihydroergotamine--stimulation of intestinal peristalsis. An experimental and clinical study.

In an experimental study in 15 beagle hounds using strain gauges a significantly increased motility in the small and large intestine after dihydroergotamine was observed. Since this assessment did not provide any information about mucus transport, gastro-intestinal passage time in patient and control groups was determined using radioopaque catheter material. While transit time in the patient group was significantly reduced by 2 x 0.5 mg DHE s.c./day, this effect was not observed in controls. We related the significantly reduced passage time after DHE in the patient group to a normalisation of a functional disturbance of regulation. The action of the drug is seen in the blocking of the stress induced increased sympathetic tone, without the side effects often seen after pure alpha-antagonists of the phentolamine type or the adrenergic guanethidine type neuronal blocking agents. The specific efficacy of DHE as a partial alpha-antagonist is pointed out. For the clinician, postoperative gastro-intestinal atony might be an indication for its use.

Modification of vascular response to synthetic oxytocin by oestrogen in rabbit.

Intravenously administered oxytocin caused a dose-related fall in blood pressure of the rabbit. When oxytocin was administered in oestrogen-primed animals, the depressor response was converted to a pressor one "Oxytocin reversal". The "oxytocin reversal." was abolished after treatment with dihydroergotamine, hexamethonium or adrenalectomy. The "oxytocin reversal" did not appear in reserpinized animals.