Péter Sándor

Nervous control of the cerebrovascular system: doubts and facts.

Increased function of the central neurons results in increased neuronal metabolism and, as a consequence, increased concentration of metabolic end-products (H+, K+, adenosin) results in an increased cerebral blood flow (CBF). There is a general agreement among investigators that products of cerebral tissue metabolism as well as chemical stimuli are key factors that determine the rate of blood flow in the brain. CBF, however, may increase out of proportion to metabolic demands, may increase without significant change in local metabolism, and may increase much faster than the accumulation of the metabolic end-products. Therefore, the 100-year-old metabolic hypothesis of Roy and Sherrington, cannot fully explain the increases of CBF during increased functional activity of the central neurons. The tight coupling of neuronal activity and blood flow in the brain is demonstrated by a large amount of data. Therefore, the likelihood exists that neurogenic stimuli via perivascular nerve endings may act as rapid initiators, to induce a moment-to-moment dynamic adjustment of CBF to the metabolic demands, and further maintenance of these adjusted parameters is ensured by the metabolic and chemical factors. Perivascular nerve endings were identified in the outer smooth muscle layer of the cerebral arteries, arterioles and veins. Their axonterminals contain a large variety of neurotransmitters, often co-localised in synaptic vesicles. Stimulation of the nerves results in a release of transmitters into the narrow neuromuscular synaptic clefts in the cerebrovascular smooth muscle, close to specific receptor sites in the vessel wall. In spite of these facts, however, and in spite of the large number of new experimental evidences, the role of the nervous control of the cerebrovascular system is underestimated both in medical textbooks and in the common medical knowledge since decades. In the last 20 years major advances have been made that make it necessary to revise this false view. The purpose of this review is to facilitate this process at the end of this century, when the importance of the nervous control of the cerebral circulation has been fully appreciated among investigators.

Prophylactic Treatment of Migraine With β‐Blockers and Riboflavin: Differential Effects on the Intensity Dependence of Auditory Evoked Cortical Potentials

Objective.– To investigate the influence of different pharmacological treatments on the intensity dependence of auditory evoked cortical potentials in migraineurs.

Contribution of poly(ADP-ribose) polymerase to postischemic blood-brain barrier damage in rats.

The nuclear enzyme poly(ADP-ribose) polymerase (PARP) is activated by oxidative stress and plays a significant role in postischemic brain injury. We assessed the contribution of PARP activation to the blood–brain barrier (BBB) disruption and edema formation after ischemia–reperfusion. In male Wistar rats, global cerebral ischemia was achieved by occluding the carotid arteries and lowering arterial blood pressure for 20 mins. The animals were treated with saline or with the PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N, N-dimethylacetamide.HCl (PJ34); (10 mg/kg, i.v.) before ischemia. After 40 mins, 24, and 48 h of reperfusion, the permeability of the cortical BBB was determined after Evans Blue (EB) and Na-fluorescein (NaF) administration. The water content of the brain was also measured. The permeability of the BBB for EB increased after ischemia–reperfusion compared with the nonischemic animals after 24 and 48 h reperfusion but PARP inhibition attenuated this increase at 48 h (nonischemic: 170 ± 9, saline: 760 ± 95, PJ34: 472 ± 61 ng/mg tissue). The extravasation of NaF showed similar changes and PJ34 post-treatment attenuated the permeability increase even at 24 h. PARP inhibition decreased the brain edema seen at 48 h. Because PARP has proinflammatory properties, the neutrophil infiltration of the cortex was determined, which showed lower values after PJ34 treatment. Furthermore, PJ34 treatment decreased the loss of the tight junction protein occludin at 24 and 48 h. The inhibition of PARP activity accompanied by reduced post-ischemic BBB disturbance and decreased edema formation suggests a significant role of this enzyme in the development of cerebral vascular malfunction.

Familial influences on cortical evoked potentials in migraine.

Cortical information processing in migraine patients is impaired between attacks, showing deficient habituation of pattern-reversal visual evoked potentials (VEP), and strong intensity dependence of auditory cortical evoked potentials (IDAP). This could be a genetic trait as certain genetic patterns are known for evoked potentials in healthy subjects. We investigated VEP habituation and IDAP in 20 pairs of migraineurs made up of parents and their children. Using a Monte-Carlo statistical method, we selectively assessed vertical familial influences. VEP habituation and IDAP were abnormal in both parents and children. However, similarity was far more pronounced between related pairs than between unrelated pairs. Familial influences are highly significant in determinants of cortical information processing in migraineurs, hence supporting the important role of genetic factors.

MR‐spectroscopic imaging during visual stimulation in subgroups of migraine with aura

Migraine pathophysiology possibly involves deficient mitochondrial energy reserve and diminished cortical habituation. Using functional magnetic resonance spectroscopic imaging (fMRSI), we studied cortical lactate changes during prolonged visual stimulation to search for different pathophysiological mechanisms in clinically distinct subgroups of migraine with aura. Eleven healthy volunteers (HV) and 10 migraine patients were investigated interictally: five with visual aura (MA) and five with visual symptoms and at least one of the following: paraesthe-sia, paresis or dysphasia (MAplus). Using MRSI (Philips, 1.5 T) 1H-spectra were repeatedly obtained from a 25 mm-thick slice covering visual and non-visual cortex, with the first and fifth measurements in darkness and the second to fourth with 8-Hz checkerboard stimulation. In MAplus lactate increased only during stimulation, only in visual cortex; in MA resting lactate was high in visual cortex, without further increase during stimulation. This is compatible with an abnormal metabolic strain during stimulation in MAplus, possibly due to dishabituation, and a predominant mitochondrial dysfunction in MA.

ZINC FORMS COMPLEXES WITH HIGHER KINETICAL STABILITY THAN CALCIUM, 5-F-BAPTA AS A GOOD EXAMPLE

Increasing interest is focused on the role of zinc in biological systems. A rapidly growing family of DNA-binding proteins contains zinc-fingers, where zinc is bound to cysteine or histidine residues. On the other hand zinc is able to displace calcium from its binding sites and in this way it may modify calcium-mediated cellular processes. In the present report dissociation rates of Zn2(+)- and Ca2(+)-complexes with 5-F-BAPTA, a widely used NMR-active calcium indicator, have been measured by two-dimensional 19F NMR exchange spectroscopic methods. The results show that the lifetime of the Zn2(+)-complex is more than five times longer than that of the Ca2(+)-complex. The longer lifetime, when combined with a higher thermodynamical stability of the Zn2+-complex, may explain why, in some cellular processes, Zn2+ can compete with Ca2+ in spite of a presumably high [Ca2+]/[Zn2+] free ion concentration ratio.

Blood-brain barrier changes during compensated and decompensated hemorrhagic shock

Dysfunction of the blood-brain barrier (BBB) can be associated with a large number of central nervous system and systemic disorders. The aim of the present study was to determine BBB changes during different phases of hemorrhagic shock. The experiments were carried out on male Wistar rats anaesthetized with urethane. To produce compensated or decompensated hemorrhagic shock, mean arterial pressure was decreased from the normotensive control values to 40 mmHg by a standardized method of blood withdrawal from the femoral artery. Cerebral blood flow changes were followed by laser-Doppler flowmetry, and arterial blood gas values were monitored over the whole procedure. Cortical blood flow was significantly reduced in compensated and in decompensated hemorrhagic shock compared with the normotensive rats. As the shock shifted to the decompensated phase, the blood flow reduction was more pronounced. BBB permeability studies using sodium fluorescein (molecular weight of 376) and Evans Blue albumin (molecular weight of 67,000) have revealed a significant increase of the BBB permeability for sodium fluorescein in the decompensated stage of hemorrhagic shock. Western blot analysis of brain capillaries showed that the expression of the transmembrane tight junction protein occludin was reduced in response to hemorrhagic shock, and the decrease of occludin was more pronounced in the decompensated phase. A similar expression pattern was shown by the transmembrane adherens junction protein cadherin as well. Our results suggest that the decompensated phase of hemorrhagic shock is associated with disturbances of the BBB, which may be explained by the dysfunction of interendothelial junctions caused by decreased occludin and cadherin levels.

Endocannabinoids in cerebrovascular regulation

The cerebral blood flow is tightly regulated by myogenic, endothelial, metabolic, and neural mechanisms under physiological conditions, and a large body of recent evidence indicates that inflammatory pathways have a major influence on the cerebral blood perfusion in certain central nervous system disorders, like hemorrhagic and ischemic stroke, traumatic brain injury, and vascular dementia. All major cell types involved in cerebrovascular control pathways (i.e., smooth muscle, endothelium, neurons, astrocytes, pericytes, microglia, and leukocytes) are capable of synthesizing endocannabinoids and/or express some or several of their target proteins [i.e., the cannabinoid 1 and 2 (CB1 and CB2) receptors and the transient receptor potential vanilloid type 1 ion channel]. Therefore, the endocannabinoid system may importantly modulate the regulation of cerebral circulation under physiological and pathophysiological conditions in a very complex manner. Experimental data accumulated since the late 1990s indicate that the direct effect of cannabinoids on cerebral vessels is vasodilation mediated, at least in part, by CB1 receptors. Cannabinoid-induced cerebrovascular relaxation involves both a direct inhibition of smooth muscle contractility and a release of vasodilator mediator(s) from the endothelium. However, under stress conditions (e.g., in conscious restrained animals or during hypoxia and hypercapnia), cannabinoid receptor activation was shown to induce a reduction of the cerebral blood flow, probably via inhibition of the electrical and/or metabolic activity of neurons. Finally, in certain cerebrovascular pathologies (e.g., subarachnoid hemorrhage, as well as traumatic and ischemic brain injury), activation of CB2 (and probably yet unidentified non-CB1/non-CB2) receptors appear to improve the blood perfusion of the brain via attenuating vascular inflammation.

Comparative effects of chloralose anesthesia and Sernylan analgesia on cerebral blood flow, CO2 responsiveness, and brain metabolism in the baboon.

A comparison was made between the effects of two different anesthetics, alpha-D-gluco-chloralose and 1-1-phenylcyclohexyl piperidine hydrochloride (Sernylan8), on cerebral blood flow (CBF), brain metabolism and cerebrovascular CO, responsiveness in primates. The experiments were carried out on immobilized and artificially ventilated baboons. Anesthesia was induced either with 100/mg/kg chloralose (i.p.) or with 1 mg/kg Sernylan (i.m.). CBF in 8 different brain regions was measured by the intra-arterial luXe clearance technique. The CO] responsiveness of the cerebrovascular bed was tested by a gas mixture containing 5% CO,. Chloralose depressed total as well as regional CBF compared to the effect of Sernylan. A significant shift occurred toward lower CBF values in the grey matter while white matter flow was identical in the two groups. Brain Oa consumption was significantly higher during Sernylan analgesia (3.35 ± 0.34 ml/100 g/min) than during chloralose anesthesia (2.42 ± 0.22 ml/100 g/min). There were no differences in glucose uptake, lactate and pyruvate production, or in arterial and cerebral venous blood gases in the two types of anesthesia. The cerebrovascular CO2 sensitivity of the Sernylan-treated baboons was higher than that of the chloralose-anesthetized animals, in both the grey and white matter.

Contribution of the heme oxygenase pathway to the maintenance of the hypothalamic blood flow during diminished nitric oxide synthesis

The cerebrovascular effects of the heme oxygenase–carbon monoxide pathway were studied in the rat hypothalamus. Intraperitoneal administration of the heme oxygenase inhibitor zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG, 45 μmol/kg) had no significant effect on the resting cerebral blood flow, but increased hypothalamic nitric oxide synthase activity by 67% without changing the CSF cyclic GMP concentration. After pharmacologic inhibition of nitric oxide synthase, the diminished cerebral blood flow was further reduced by 22% after administration of ZnDPBG, and the effect showed direct correlation with the baseline perfusion level. Therefore, endogenous carbon monoxide may significantly contribute to the cerebral vasoregulation under resting conditions and in pathophysiologic states associated with diminished nitric oxide synthesis.