Memantine mediates neuroprotection via regulating neurovascular unit in a mouse model of focal cerebral ischemia.

AIMS: Memantine is a low-moderate affinity and uncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonist, which is also a potential neuroprotectant in acute ischemic stroke for its particular action profiles. The present study was to reveal the mechanisms involved in the neuroprotection of memantine. MAIN METHODS: We used a mouse model of permanent focal cerebral ischemia via middle cerebral artery occlusion to verify our hypothesis. 2,3,5-Triphenyltetrazolium chloride staining was used to compare infarct size. The amount of astrocytes and the somal volume of the microglia cell body were analyzed by immunohistochemistry and stereological estimates. Western blotting was used to determine the protein expressions. KEY FINDINGS: Memantine prevented cerebral ischemia-induced brain infarct and neuronal injury, and reduced oxygen-glucose deprivation-induced cortical neuronal apoptosis. Moreover, memantine reduced the amount of the damaged astrocytes and over activated microglia after 24h of ischemia. In the early phase of ischemia, higher production of MMP-9 was observed, and thereby collagen IV was dramatically disrupted. Meanwhile, the post-synaptic density protein 95(PSD-95) was also severely cleavaged. Memantine decreased MMP-9 secretion, prevented the degradation of collagen IV in mouse brain. PSD-95 cleavage was also inhibited by memantine. SIGNIFICANCE: These results suggested that memantine exerted neuroprotection effects in acute ischemic brain damage, partially via improving the functions of neurovascular unit. Taking all these findings together, we consider that memantine might be a promising protective agent against ischemic stroke.

[Pathophysiology of cluster headache]. / Physiopathologie de l'algie vasculaire de la face (AVF).

The aetiology of cluster headache is partially unknown. Three areas are involved in the pathogenesis of cluster headache: the trigeminal nociceptive pathways, the autonomic system and the hypothalamus. The cluster headache attack involves activation of the trigeminal autonomic reflex. A dysfunction located in posterior hypothalamic gray matter is probably pivotal in the process. There is a probable association between smoke exposure, a possible genetic predisposition and the development of cluster headache.

Patterned optogenetic modulation of neurovascular and metabolic signals.

The hemodynamic and metabolic response of the cortex depends spatially and temporally on the activity of multiple cell types. Optogenetics enables specific cell types to be modulated with high temporal precision and is therefore an emerging method for studying neurovascular and neurometabolic coupling. Going beyond temporal investigations, we developed a microprojection system to apply spatial photostimulus patterns in vivo. We monitored vascular and metabolic fluorescence signals after photostimulation in Thy1-channelrhodopsin-2 mice. Cerebral arteries increased in diameter rapidly after photostimulation, while nearby veins showed a slower smaller response. The amplitude of the arterial response was depended on the area of cortex stimulated. The fluorescence signal emitted at 450/100 nm and excited with ultraviolet is indicative of reduced nicotinamide adenine dinucleotide, an endogenous fluorescent enzyme involved in glycolysis and the citric acid cycle. This fluorescence signal decreased quickly and transiently after optogenetic stimulation, suggesting that glucose metabolism is tightly locked to optogenetic stimulation. To verify optogenetic stimulation of the cortex, we used a transparent substrate microelectrode array to map cortical potentials resulting from optogenetic stimulation. Spatial optogenetic stimulation is a new tool for studying neurovascular and neurometabolic coupling.

Jugular venous overflow of noradrenaline from the brain: a neurochemical indicator of cerebrovascular sympathetic nerve activity in humans.

A novel neurochemical method was applied for studying the activity of sympathetic nerves in the human cerebral vascular system. The aim was to investigate whether noradrenaline plasma kinetic measurements made with internal jugular venous sampling reflect cerebrovascular sympathetic activity. A database was assembled of fifty-six healthy subjects in whom total body noradrenaline spillover (indicative of whole body sympathetic nervous activity), brain noradrenaline spillover and brain lipophlic noradrenaline metabolite (3,4-dihydroxyphenolglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG)) overflow rates were measured. These measurements were also made following ganglion blockade (trimethaphan, n = 6), central sympathetic inhibition (clonidine, n = 4) and neuronal noradrenaline uptake blockade (desipramine, n = 13) and in a group of patients (n = 9) with pure autonomic failure (PAF). The mean brain noradrenline spillover and brain noradrenaline metabolite overflow in healthy subjects were 12.5 +/- 1.8, and 186.4 +/- 25 ng min(-1), respectively, with unilateral jugular venous sampling for both. Total body noradrenaline spillover was 605.8 ng min(-1) +/- 34.4 ng min(-1). As expected, trimethaphan infusion lowered brain noradrenaline spillover (P = 0.03), but perhaps surprisingly increased jugular overflow of brain metabolites (P = 0.01). Suppression of sympathetic nervous outflow with clonidine lowered brain noradrenaline spillover (P = 0.004), without changing brain metabolite overflow (P = 0.3). Neuronal noradrenaline uptake block with desipramine lowered the transcranial plasma extraction of tritiated noradrenaline (P = 0.001). The PAF patients had 77% lower brain noradrenaline spillover than healthy recruits (P = 0.06), indicating that in them sympathetic nerve degeneration extended to the cerebral circulation, but metabolites overflow was similar to healthy subjects (P = 0.3). The invariable discordance between noradrenline spillover and noradrenaline metabolite overflow from the brain under these different circumstances indicates that the two measures arise from different sources, i.e. noradrenaline spillover originates from the cerebral vasculature outside the blood-brain barrier, and the noradrenaline metabolites originate primarily from brain noradrenergic neurons. We suggest that measurements of transcranial plasma noradrenaline spillover have utility as a method for assessing the sympathetic nerve activity of the cerebral vasculature.

Sympathetic nerve activity in the superior cervical ganglia increases in response to imposed increases in arterial pressure.

Sympathetic vasoconstriction of cerebral vessels has been proposed to be a protective mechanism for the brain, limiting cerebral perfusion and microcirculatory pressure during transient increases in arterial pressure. To furnish direct neural evidence for this proposition, we aimed to develop a method for recording cerebral sympathetic nerve activity (SNA) from the superior cervical ganglion (SCG). We hypothesized that SNA recorded from the SCG increases during imposed hypertension, but not during hypotension. Lambs (n = 11) were anesthetized (alpha-chloralose, 20 mg.kg(-1).h(-1)) and ventilated. SNA was measured using 25-microm tungsten microelectrodes inserted into the SCG. Arterial blood pressure (AP) was pharmacologically raised (adrenaline, phenylephrine, or ANG II, 1-50 microg/kg iv), mechanically raised (intravascular balloon in the thoracic aorta), or lowered (sodium nitroprusside, 1-50 microg/kg iv). In response to adrenaline (n = 10), mean AP increased 135 +/- 10% from baseline (mean +/- SE), and the RMS value of SNA (Square Root of the Mean of the Squares, SNA(RMS)) increased 255 +/- 120%. In response to mechanically induced hypertension, mean AP increased 43 +/- 3%, and SNA(RMS) increased 53 +/- 13%. Generally, (9 of 10 animals), SNA(RMS) did not increase, as AP was lowered with sodium nitroprusside. Using a new model for direct recording of cerebral SNA from the SCG, we have demonstrated that SNA increases in response to large induced rises, but not falls, in AP. These findings furnish direct support for the proposed protective role for sympathetic nerves in the cerebral circulation.

[Possibilites to improve the cerebral venous tonus in patients suffering of accelerated ageing in blood circulation system by the nonmedicamentousal sympathocorrection method]. / Vozmozhnosti nemedikamentoznoi simpatokorrektsii tonusa mozgovykh ven u lits s priznakami uskorennogo stareniia v sisteme krovoobrashcheniia.

The aim of the study was to evaluate the effectiveness of the transdermal electro impulses directed on ganglions stellatum in order to prevent the accelerated ageing and improve the cerebral venous flow. Using by the angioscanning method it was been found the phenomenon of ectasia in venae jugularis int. in patients suffering of accelerated ageing in 100% cases. The normalization of venous diameter after the treatment by electrical impulses has been found in 31-55% of cases.

Topographic microsurgical anatomy of the paraclinoid carotid artery.

In this publication, the authors describe the microanatomic topography of the entire paraclinoid area with respect to the paraclinoid segment of the internal carotid artery and its surrounding anatomical structures. Special attention was given to the borders of the paraclinoid area, cavernous sinus, arterial vessels, and cranial nerves passing through the region. The paraclinoid region was defined as a pyramid-formed space formed by the dural covering of the anterior clinoid process. The superior border is formed by the continuity of the anterior petroclinoid fold, anteriorly on the superior surface of the anterior clinoid process and medially in the direction of the diaphragma sellae. This dural sheet encircles the internal carotid artery and forms the so-called distal dural ring of the internal carotid artery. The medial border of the paraclinoid region is formed by the body of the sphenoid bone and the adjacent periosteal sheet. The inferior border is formed by a fibrous plate between the middle and anterior clinoid processes. This so-called proximal dural ring separates the venous compartments of the cavernous area from the paraclinoid area. The lateral border is formed by the lateral surface of the anterior clinoid process with its dural covering. The arterial supply of this region is provided by branches of the intracavernous carotid segment and the ophthalmic artery. The important nerves in close vicinity to the paraclinoidal area are the optic and the oculomotor nerves. Understanding and knowledge of the topographic anatomy of the paraclinoid area is essential for microsurgical exposure of this region.

Nitric oxide is the predominant mediator for neurogenic vasodilation in porcine pial veins.

The innervation pattern and the vasomotor response of the potential transmitters in the porcine pial veins were investigated morphologically and pharmacologically. The porcine pial veins were more densely innervated by vasoactive intestinal polypeptide (VIP)- and neuropeptide Y-immunoreactive (I) fibers than were calcitonin gene-related peptide (CGRP)-I, choline acetyltransferase-I, Substance P (SP)-I, and NADPH diaphorase fibers. Serotonin (5-HT)-I fibers, which were not detected in normal control pial veins, were observed in isolated pial veins after incubation with 5-HT (1 microM). 5-HT-I fibers, however, were not observed when incubation with 5-HT was performed in the presence of guanethidine (1 microM), suggesting that 5-HT was taken up into the sympathetic nerves. In vitro tissue bath studies demonstrated that porcine pial veins in the presence of active muscle tone relaxed on applications of exogenous 5-HT, CGRP, SP, VIP, and sodium nitroprusside, whereas exogenous norepinephrine and neuropeptide Y induced only constrictions. Transmural nerve stimulation (TNS) did not elicit any response in pial veins in the absence of active muscle tone. However, in the presence of active muscle tone, pial veins relaxed exclusively on TNS. This tetrodotoxin-sensitive relaxation was not affected by receptor antagonists for VIP, CGRP, 5-HT, or SP but was blocked by L-glutamine (1 mM) and abolished by Nomega-nitro-L-arginine (10 microM) and Nomega-nitro-L-arginine methyl ester (10 microM). The inhibition by L-glutamine, Nomega-nitro-L-arginine, and Nomega-nitro-L-arginine methyl ester was reversed by L-arginine and L-citrulline but not by their D-enantiomers. These results demonstrate that the vasomotor effect of all potential transmitters except 5-HT in the pial veins examined resembles that in cerebral arteries. Although porcine pial veins receive vasodilator and constrictor nerves, a lack of constriction on TNS suggests that the dilator nerves that release nitric oxide may play a predominant role in regulating porcine pial venous tone.

The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation.

Primary headache syndromes, such as cluster headache and migraine, are widely described as vascular headaches, although considerable clinical evidence suggests that both are primarily driven from the brain. The shared anatomical and physiologic substrate for both of these clinical problems is the neural innervation of the cranial circulation. Functional imaging with positron emission tomography has shed light on the genesis of both syndromes, documenting activation in the midbrain and pons in migraine and in the hypothalamic gray in cluster headache. These areas are involved in the pain process in a permissive or triggering manner rather than as a response to first-division nociceptive pain impulses. In a positron emission tomography study in cluster headache, however, activation in the region of the major basal arteries was observed. This is likely to result from vasodilation of these vessels during the acute pain attack as opposed to the rest state in cluster headache, and represents the first convincing activation of neural vasodilator mechanisms in humans. The observation of vasodilation was also made in an experimental trigeminal pain study, which concluded that the observed dilation of these vessels in trigeminal pain is not inherent to a specific headache syndrome, but rather is a feature of the trigeminal neural innervation of the cranial circulation. Clinical and animal data suggest that the observed vasodilation is, in part, an effect of a trigeminoparasympathetic reflex. The data presented here review these developments in the physiology of the trigeminovascular system, which demand renewed consideration of the neural influences at work in many primary headaches and, thus, further consideration of the physiology of the neural innervation of the cranial circulation. We take the view that the known physiologic and pathophysiologic mechanisms of the systems involved dictate that these disorders should be collectively regarded as neurovascular headaches to emphasize the interaction between nerves and vessels, which is the underlying characteristic of these syndromes. Moreover, the syndromes can be understood only by a detailed study of the cerebrovascular physiologic mechanisms that underpin their expression.

No relation between cephalic venous dilatation and pain in migraine.

Evidence for the involvement of the cranial arterial system in migraine is plentiful, but it is unclear whether the cranial venous system may be involved in the mechanism of migraine pain. Venules are the preferentially involved vessels in the neurogenic inflammation animal model of migraine. The cranial and cerebral veins and sinuses are pain sensitive and receive sensory innervation from the trigeminal nerve. If the veins are involved in migraine pathogenesis, a venous dilatation would presumably be painful. The effect of a short lasting cranial venous dilatation, induced by applying pressure on the internal jugular veins (Queckenstedt's manoeuvre), was therefore compared with a placebo procedure, consisting of an equal pressure applied on to the lateral aspect of the neck. In each procedure pressure was applied for 10 seconds. The study used a single blind, randomised, cross over design, and 20 patients with an acute attack of migraine without aura participated. After each procedure, headache intensity was rated on a standardised five point scale. After Queckenstedt's manoeuvre 40% of the patients reported no change in headache intensity, 25% a worsening, and 35% an improvement of their headache. No significant difference between the headache intensity ratings during Queckenstedt's manoeuvre and the placebo manoeuvre was found (p=0.22). The findings make it unlikely that the cephalic venous system is of major importance in migraine pain mechanisms and, therefore, also less likely that neurogenic inflammation plays a significant part in humans during attacks of migraine without aura.

Sympathetic and sensory innervation of the extracerebral vasculature: roles for p75NTR neuronal expression and nerve growth factor.

The extracerebral vasculature receives a postnatal innervation of noradrenergic sympathetic axons and nociceptive sensory axons. These axons are responsive to the neurotrophin nerve growth factor (NGF), in that they possess the transmembrane receptors p140proto-trkA and p75neurotrophin receptor (NTR) which bind NGF. p75NTR-deficient mice display reduced patterns of sympathetic innervation of the pineal gland and sensory innervation of the skin (Lee et al., 1992, 1994a). The goal of this investigation was to determine whether an absence of p75 expression likewise perturbs the sympathetic and sensory innervation of the extracerebral vessels of adult mice, and if so, whether increasing levels of NGF within the target field is capable of enhancing this perturbed axon growth. Four lines of mice were used: wild-type C57Bl/6 mice, transgenic mice overexpressing NGF in the brain, p75NTR-deficient mice, and hybrid mice which overexpress NGF in the brain but lack p75NTR expression. Sympathetic and sensory innervation of the meningeal arteries were severely perturbed in p75NTR-deficient mice. Wild-type and hybrid mice displayed comparable patterns of sympathetic and sensory axons along the dural arteries. Transgenic mice, however, possessed the greatest degree of arterial innervation. These data reveal that while p75NTR expression may be a critical factor for initiating axon growth along the extracerebral vasculature during postnatal development, the sympathetic and sensory nervous systems display a remarkable degree of NGF-induced axonal plasticity, such that increased levels of NGF can ameliorate perturbed patterns of arterial innervation in p75-deficient mice.

L-citrulline conversion to L-arginine in sphenopalatine ganglia and cerebral perivascular nerves in the pig.

The presence of nitric oxide synthase (NOS), argininosuccinate synthetase (ASS), and argininosuccinate lyase (ASL) and their coexistence with NADPH-diaphorase (NADPHd), a marker for NOS, in the porcine sphenopalatine ganglia (SPG), pial veins, and the anterior cerebral arteries was examined using immunohistochemical and histochemical staining techniques. NOS-immunoreactive (I), ASS-I, and ASL-I fibers were found in pial veins and the anterior cerebral arteries. NOS, ASS, and ASL immunoreactivities were also found in neuronal cell bodies in the SPG. Almost all neuronal cell bodies in the SPG and nerve fibers in pial veins and the anterior cerebral arteries that were reactive to ASS, ASL, and NOS were also stained positively with NADPHd, suggesting that ASS, ASL, and NOS were colocalized in the same neurons in the SPG and perivascular nerves. With the use of in vitro tissue bath techniques, L-citrulline but not D-citrulline reversed inhibition of neurogenic vasodilation in isolated porcine pial veins produced by NOS inhibitors such as NG-nitro-L-arginine methyl ester. In the presence of L-aspartate, L-arginine was synthesized from L-citrulline in homogenates of SPG and endothelium-denuded cerebral arteries and pial veins. These results provide evidence indicating that perivascular nerves in pial veins like cerebral arteries can convert L-citrulline to L-arginine for synthesizing nitric oxide. The conversion is most likely via an argininosuccinate pathway.

The sympathetic nerves of the parasellar region: pathways to the orbit and the brain.

Sympathetic nerves innervate targets in the orbit and the brain. They issue from the superior cervical ganglion and reach the parasellar region via the internal carotid nerve. Information on their further parasellar course and distribution is scant and contradictory. In this study the parasellar sympathetic pathways of 30 human infants and 6 human fetuses were investigated by microdissection and histologically. A common parasellar sympathetic trunk, which reunites all the nerve fibers emanating from the lateral and medial internal carotid plexus, is described as well as its further divisions. It was found that the posterior knee of the infant carotid siphon is free of large sympathetic nerve bundles. In addition a ganglion is described, which is situated in the parasellar adipose body. It is reached by nerve fibers coming from the parasellar sympathetic pathways. Fibers that issue from this ganglion join the periorbita and the orbital muscle of Müller. These anatomical facts are of immediate importance for preventing nerve damage during cavernous sinus surgery. Furthermore, the study improves the anatomical knowledge of the parasellar region and suggests a new concept for the innervation of the orbital muscle.

The physiology of the cerebrovascular parasympathetic innervation.

The parasympathetic innervation to the cerebral vessels has only recently begun to be investigated in detail and to be understood in terms of the control of brain function. Much of the experimental work has been motivated by the potent vasoactive potential of the parasympathetic fibres, which can produce profound increases in cerebral blood flow (CBF) when electrically stimulated. This paper first outlines the principal anatomical and biochemical evidence for the origins and pathways of the parasympathetic fibres and the basis of their influence on CBF. Next, studies performed to elucidate their physiological function are reviewed, and finally their possible functional significance is discussed in relation to normal and pathophysiological brain function and their possible involvement in the trigeminovascular system.

The peptidergic innervation of human coronary and cerebral vessels.

It is now well established that in addition to nerves containing classical transmitters, the mammalian vascular system is also supplied by nerve fibre subpopulations containing several vasoactive peptides. The precise function of these peptides (neuropeptide Y, calcitonin gene-related peptide, vasoactive intestinal polypeptide, somatostatin and the tachykinins) is still unknown, however, their widespread occurrence in perivascular nerves indicates that they are likely candidates for a role in the neurogenic regulation of the vascular system. It has been suggested that they may exert a direct vasomotor action via their own receptors and/or modulate the release and action of other vascular transmitters. Recently, several studies have focused on the supply of nerve fibres storing neuropeptides in the coronary and cerebral vasculature of laboratory animals, however, little is known on the distribution of these putative transmitters in human coronary and cerebral vessels. In this paper, the immunocytochemical evidence that several neuropeptides are localized in subpopulations of afferent and efferent nerve fibres supplying the human coronary and cerebral vasculature is focused.

Nitrergic innervation of rat brain vasculature.

Nitric oxide synthase has been located in the brain, in several neuronal populations which appear in close contact either with the microvasculature or the external surface of extracerebral vessels. These data provide structural support to the pharmacological evidences of the nitric oxide participation in the regulation of vascular tone of brain blood vessels.

Effect of cervical sympathectomy and hypoxia on the heterogeneity of O2 saturation of small cerebrocortical veins.

This study evaluated the hypothesis that the sympathetic nervous system was one of the factors increasing the heterogeneity of cerebrocortical venous O2 saturation and this heterogeneity would be greater during hypoxia when cervical sympathetic activity was elevated. Thirty-two male Long-Evans rats were either sham operated (n = 16) or received bilateral cervical sympathectomy (n = 16). One-half of the animals (n = 8) in each treatment were challenged by hypoxia (8% O2 in N2). Cerebral blood flow was determined in five brain regions with [14C]iodoantipyrine. Oxygen saturation was measured microspectrophotometrically in small cerebrocortical arteries and veins. The degree of hypoxic hyperemia was not significantly different between sham-operated and sympathectomized rats. Cortical venous O2 saturations, indicating the balance between O2 supply and consumption, were significantly more heterogeneous in the sham-operated group under both normoxic and hypoxic conditions. The coefficient of variation (CV = 100 x SD/mean) for the normoxic sham-operated animals was 24.9% and the average venous O2 saturation was 53.8%. During hypoxia, venous O2 saturation was significantly decreased to 43.1% without a change in CV (24.5%). Sympathectomy significantly reduced this heterogeneity through a reduction in the number of low O2 saturation veins (CV = 13.2%) under normoxic conditions and the effect was similar under hypoxic conditions (CV = 15.3%). In both sham-operated and sympathectomized groups, hypoxia elicited a significantly higher cerebrocortical O2 consumption. Thus, bilateral cervical sympathectomy improved the O2 supply in selective cerebrocortical regions with high O2 extraction. However, the effect of sympathetic innervation on the heterogeneity of cerebrocortical venous O2 saturation was not potentiated by hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Small pial vessels, but not choroid plexus, exhibit specific biochemical correlates of functional cholinergic innervation.

In an attempt to provide the biochemical foundations for a putative cholinergic innervation of small pial vessels and choroid plexus, we have assessed their ability to specifically accumulate choline, synthesize and release acetylcholine (ACh) in response to depolarization. Our results show that both small pial vessels and choroid plexus avidly accumulate choline via a sodium-dependent mechanism which could be inhibited by hemicholinium-3 (IC50 in pial vessels = 47.8 microM). Light microscopic examination of radioautographs from vessels incubated with [3H]choline revealed two distinct sites of accumulation in the vessel wall. One site probably corresponded to nerve terminals and the other was closely associated with the endothelial cells. In small pial vessels, a major proportion (60%-70%) of the choline acetyltransferase (ChAT) activity could be inhibited by 4-naphthylvinylpyridine (4-NVP), a potent inhibitor of neuronal ChAT; and, following either K+ or veratridine depolarization, a Ca2(+)-dependent release of authentic [3H]ACh could be measured. In contrast, the choroid plexus exhibited a rather low ChAT activity which was not inhibited by 4-NVP and no release of ACh could be detected in this tissue following depolarization. Altogether, the results of the present study show that (1) small pial vessels exhibit all the most selective biochemical markers that are characteristic of cholinergic nerves; (2) [3H]choline in pial vessels can be accumulated in non-neuronal elements which probably correspond to the endothelial cells; and (3) the choroid plexus failed to exhibit convincing biochemical markers that would attest in favor of a functional cholinergic innervation.(ABSTRACT TRUNCATED AT 250 WORDS)