不典型结核性脑膜炎25例临床分析

目的 总结不典型结核性脑膜炎的诊断方法,以避免误诊.方法 结合临床表现、脑脊液、影像学等辅助检查,回顾性分析25例不典型结脑的临床资料.结果 25例患者临床表现多无特异性,与其它颅内感染及脑血管痛难以鉴别,只有综合分析,才能得以确诊.结论 在缺乏典型临床表现情况下,脑脊液反复检查可呈典型改变,影像学检查对诊断有重要意义.     

Dilatation induced by 5-HT in the middle meningeal artery of the anaesthetised cat

In chloralose-anaesthetised cats, we studied the effects of intravenous and intra-carotid injections of 5-HT on the middle meningeal artery and the way these were modified by 5-HT antagonists. Cats were prepared for blood pressure recording and intravenous injections and a catheter inserted into one carotid artery via a lingual artery. The middle meningeal arteries were exposed and blood flow recorded with laser Doppler probes. Intravenous injections of 5-HT, 2–50 µg kg^–1 (5.2–129 nmole kg^–1), produced a dose-dependent fall in blood pressure, a rise in meningeal blood flow, and an associated fall in middle meningeal resistance. Resistance changes were the result of a local dilatation and not due to changes downstream of the recording probe. Intracarotid injections of 5-HT produced similar systemic and craniovascular responses, which were larger in the ipsilateral middle meningeal artery. Dose-response curves of vascular resistance changes to intravenous injection of 5-HT were not significantly affected by WAY100635 (5-HT_1A antagonist), GR127935 (5-HT_1B/1D antagonist), methiothepin (5-HT_2C and 5-HT₇ antagonist), ketanserin (5-HT_2A antagonist), SB203186 (5-HT₄ antagonist) or cervical sympathectomy, but were blocked by the 5-HT_3/4 antagonist tropisetron, the 5-HT₃ antagonist ondansetron, the ganglion-blocking drug hexamethonium and by vagotomy. These drugs and procedures did not significantly antagonise the response to intra-arterially injected 5-HT. We conclude that intravenously-administered 5-HT is a vasodilator in vivo in the cat dural circulation, and that the dilation is not mediated by 5-HT₁, 5-HT₂, 5-HT₄ or 5-HT₇ receptors, but is primarily mediated by a vagal reflex, initiated via 5-HT₃ receptor activation and brought about by an increase in parasympathetic tone to the middle meningeal artery as part of the von Bezold-Jarisch reflex. There also appears to be a direct vasodilator effect mediated by unknown receptor types, particularly after intra-arterial administration. Neither of these effects is, however, likely to be of importance in the pathophysiology of migraine or other vascular headaches.     

不同降温方法治疗结核性脑膜炎高热效果比较

目的探讨不同降温方法用于结核性脑膜炎高热患者的临床效果。方法35例结核性脑膜炎高热患者分成观察组（11例）和对照组（24例），对照组实施传统降温法，观察组实施亚低温降温方法，观察两组降温前后生命体征、颅内压、Glasgow评分、并发症及病死率情况。结果观察组有效率81．8％，对照组为41．7％，两组比较差异有统计学意义（P〈0．05）；降温后，观察组生命体征优于对照组，颅内压、病死率低于对照组（P〈0．05），Glasgow评分高于对照组（P〈0．05）；两组并发症发生率比较差异无统计学意义（P〉0．05）。结论亚低温降温法能有效控制结核性脑膜炎高热患者的体温，提高患者意识状态，降低病死率。     

RESPONSES OF THE DURAL CIRCULATION TO ELECTRICAL STIMULATION OF THE TRIGEMINAL GANGLION IN THE CAT

1. In cats anaesthetized with a-chloralose, electrical stimulation (ES) of the trigeminal ganglion produced a fall in blood pressure, a predominantly ipsilateral dilatation in the common carotid vascular bed and bilateral dilatation of the middle meningeal vascular bed. Section of the trigeminal root abolished these responses. 2. Dilatation in the middle meningeal artery was not affected by section of the cervical sympathetic trunk nor by the section of the seventh cranial nerve trunk. The dilator response was abolished by section of the spinal cord at the C3 level and by intravenous administration of bretylium (10 mg/kg) or phentol-amine (5 mg/kg). The response was significantly reduced by the prior administration of papaverine (10 mg/kg). 3. Functional adrenalectomy by means of a snare placed around the nerves and blood vessels supplying the adrenal glands significantly reduced the response. Electrical stimulation of the trigeminal ganglion was accompanied by a fall in circulating levels of noradrenaline and serotonin. 4. We conclude that ES of the trigeminal ganglion produces dilatation in the middle meningeal artery partly by autoregu-lation during the trigeminal depressor response and partly by a reduction in the circulating levels of noradrenaline. It differs from the dilatation seen in the general carotid circulation and the cortical microcirculation, which is mediated by parasympathetic nerves. There is no evidence that antidromic release of neuropeptides from sensory nerve endings in the dura plays a part in the dilatation.     

Pharmacologic strategies for the treatment of meningeal malignancy

Summary There have been significant strides in the treatment and prevention of meningeal cancer, particularly meningeal leukemia, during the past thirty years. These advantages are a direct result of innovative therapeutic approaches specifically designed to overcome the limitations of systemically administered chemotherapy. Such approaches include the administration of intrathecal chemotherapy by intralumbar or intraventricular injection, the administration of very high-dose systemic chemotherapy, and the administration of cranial or craniospinal irradiation. A better understanding of the central nervous system pharmacokinetics of commonly used anticancer agents has also resulted in improvements in the treatment of meningeal cancer. In this article, the clinical pharmacology of the most commonly used intrathecal agents and pharmacologic strategies for the treatment of meningeal cancer will be discussed. In addition, an overview of new agents for intrathecal administration and other novel CNS targeted therapies will be presented. Address for offprints: Susan M. Blaney, Texas Children's Cancer Center, 6621 Fannin, MC 3-3320, Houston, TX 77030, USA     

小鼠不完全性脑缺血、再灌注时脑膜血流量的变化及尼莫地平的作用

目的：观察双侧颈总动脉阻断后脑血流的变化。方法：结扎双侧颈总动脉观察小鼠不完全性脑缺血及其再灌注时脑膜血流量的变化。结果：结扎颈总动脉后小鼠脑膜血流量在几秒钟内骤然下降，血流量较结扎前降低约８５．９％±６．４５％。同时血管中红细胞运动近停滞状态，血管再通时脑血流处于低灌注状态，血流量下降３４．４７％±１１．６９％，此时脑缺血再灌后脑组织实际上处于一种慢性缺血状态。再灌注１０ｄ后，小鼠脑海马ＣＡ１区神经细胞数明显减少。尼莫地平可以解除再灌注时的脑血流低灌状态。并防止由此所引起的脑海马ＣＡ１区神经细胞的缺失。结论：缺血后及时给予尼莫地平具有积极的治疗意义。     

经鼻蝶入路鞍区病灶切除术后应用人工脑膜重建颅底的方法研究

目的探讨经蝶病灶切除手术中应用人工脑膜重建颅底的应用方法。方法回顾性分析人工脑膜在32例经蝶鞍区病灶术后颅底重建手术中的应用,对其修补方法及效果进行分析。结果术后头颅CT检查未见与人工脑膜有关的异常表现,减少了经蝶手术并发症,未出现新的人工脑膜相关并发症。结论人工脑膜在经蝶病灶切除手术中应用安全,能够发挥有效的作用。     

清脑片对小鼠脑膜微循环及血瘀模型的影响

目的 观察清脑片对小鼠脑膜微循环及血瘀模型的影响。方法 60只昆明种小鼠,SPF级,♀♂各半,随机分为清脑片组、脑络通组（高、中、低剂量脑络通胶囊混悬液）、空白组及模型组6组,灌服给药,空白组及模型组灌服同体积的生理盐水,连续给药10 d,记录小鼠平静后2 min内的血流灌注量。取结扎（空白组做假手术）前110~120 s的血流灌注量平均值作为结扎前的平均灌注量,取230~240 s的血流灌注量平均值作为结扎后的平均灌注量,并进行分析。另取60只KM小鼠,SPF级,♀♂各半,随机分为6组,给药方法同前,每天给药1次,连续灌服15 d。除空白组每天后腿肌注生理盐水外,其他5组每天后腿肌注地塞米松0.8 mg·kg^-1,连续肌注15 d。于第16天灌药及肌注后1 h,小鼠摘眼球取血,测全血黏度。结果 与空白组比较,模型组脑膜微循环血流量显著减少（P<0.01）。脑络通组和清脑片高剂量组可显著改善双侧颈总动脉结扎所致的小鼠脑血流量减少（P<0.01）;清脑片中剂量明显改善双侧颈总动脉结扎所致的小鼠脑血流量减少（P<0.05）。高剂量清脑片组可显著降低高切和中切黏度（P<0.01）,中剂量清脑片组可明显减低高切和中切黏度（P<0.05）;高、中剂量清脑片组可明显降低低切黏度（P<0.05）。结论 清脑片对小鼠脑膜微循环以及小鼠血瘀模型有良好的改善作用。     

脑脊液置换加鞘内给药治疗结核性脑膜炎的临床疗效评价

目的了解脑脊液置换加鞘内给药对结核性脑膜炎的治疗效果。方法选取符合条件的80例结核性脑膜炎患者,随机分为两组,对照组36例采用常规治疗,治疗组44例在常规治疗的基础上采用脑脊液置换加鞘内给药,比较2组临床疗效、脑脊液压力、脑脊液蛋白含量改变及患者预后。结果治疗组治愈率为72.73%,总有效率为93.18%,明显高于对照组的52.78%和72.22%(P<0.05),同时脑脊液压力及蛋白含量的降低均比对照组明显(P<0.05)。结论脑脊液置换加用鞘内给药治疗结核性脑膜炎,可显著提高临床疗效,有助于改善患者预后,减少并发症,是一种简单易行、安全可靠的治疗方法。     

Sensory nitrergic meningeal vasodilatation and non-nitrergic plasma extravasation in anaesthesized rats

The aim of the present study was to evaluate the role of nitric oxide (NO) of sensory neural origin in neurogenic inflammatory response in the trigeminovascular system. Antidromic vasodilatation and plasma extravasation in response to electrical stimulation (15 V, 5 Hz, 0.5 ms, 100 impulses) of the trigeminal ganglion were investigated in the dura mater and nasal mucosa/upper eyelid by laser Doppler flowmetry and [(125)I]-labelled bovine serum albumin, respectively. Electrical stimulation of the trigeminal ganglion of rats elicited a reproducible ipsilateral enhancement of both meningeal and nasal mucosal blood flow. N(omega)-nitro-L-arginine (L-NNA; 4, 8, and 16 mg/kg, i.v.), a nonselective inhibitor of nitric oxide synthase (NOS), inhibited antidromic vasodilatation both in the dura mater (15.86+/-2.05%, 22.82+/-2.51%, and 36.28+/-4.37%) and nasal mucosa (35.46+/-8.57%, 58.72+/-9.2%, and 89.99+/-8.94%) in a dose-dependent manner. Specific inhibitors of neuronal NOS, 7-nitroindazole (7-NI; 20 mg/kg, i.v.) and 3-bromo-7-nitroindazole (3Br-7NI; 10 mg/kg, i.v.) were administered to assess the possible role of NO released from the trigeminal sensory fibres. The meningeal vasodilatation was inhibited by both 3Br-7NI and 7-NI (63.36+/-7.7% and 49+/-6.5%, respectively). The nasal hyperaemic response was also reduced by 3Br-7NI (78.26+/-8.7%). Plasma extravasation in the dura mater and upper eyelid evoked by electrical stimulation of the trigeminal ganglion (25 V, 5 Hz, 0,5 ms, 5 min), expressed as extravasation ratios (ERs) of the stimulated vs. nonstimulated sides, was 1.80+/-0.8 and 4.63+/-1.24, respectively. This neurogenic oedema formation was not inhibited by neither L-NNA nor 3Br-7NI. It is concluded that neural nitrergic mechanisms are involved in the meningeal vasodilatation evoked by electrical stimulation of the trigeminal ganglion.     

Pharmacological characterisation of capsaicin-induced relaxations in human and porcine isolated arteries

Capsaicin, a pungent constituent from red chilli peppers, activates sensory nerve fibres via transient receptor potential vanilloid receptors type 1 (TRPV1) to release neuropeptides like calcitonin gene-related peptide (CGRP) and substance P. Capsaicin-sensitive nerves are widely distributed in human and porcine vasculature. In this study, we examined the mechanism of capsaicin-induced relaxations, with special emphasis on the role of CGRP, using various pharmacological tools. Segments of human and porcine proximal and distal coronary arteries, as well as cranial arteries, were mounted in organ baths. Concentration response curves to capsaicin were constructed in the absence or presence of the CGRP receptor antagonist olcegepant (BIBN4096BS, 1 μM), the neurokinin NK₁ receptor antagonist L-733060 (0.5 μM), the voltage-sensitive calcium channel blocker ruthenium red (100 μM), the TRPV1 receptor antagonist capsazepine (5 μM), the nitric oxide synthetase inhibitor N ^ω-nitro-l-arginine methyl ester HCl (l-NAME; 100 μM), the gap junction blocker 18α-glycyrrhetinic acid (10 μM), as well as the RhoA kinase inhibitor Y-27632 (1 μM). Further, we also used the K⁺ channel inhibitors 4-aminopyridine (1 mM), charybdotoxin (0.5 μM) + apamin (0.1 μM) and iberiotoxin (0.5 μM) + apamin (0.1 μM). The role of the endothelium was assessed by endothelial denudation in distal coronary artery segments. In distal coronary artery segments, we also measured levels of cyclic adenosine monophosphate (cAMP) after exposure to capsaicin, and in human segments, we also assessed the amount of CGRP released in the organ bath fluid after exposure to capsaicin. Capsaicin evoked concentration-dependent relaxant responses in precontracted arteries, but none of the above-mentioned inhibitors did affect these relaxations. There was no increase in the cAMP levels after exposure to capsaicin, unlike after (exogenously administered) α-CGRP. Interestingly, there were significant increases in CGRP levels after exposure to vehicle (ethanol) as well as capsaicin, although this did not induce relaxant responses. In conclusion, the capsaicin-induced relaxations of the human and porcine distal coronary arteries are not mediated by CGRP, NK₁, NO, vanilloid receptors, voltage-sensitive calcium channels, K⁺ channels or cAMP-mediated mechanisms. Therefore, these relaxant responses to capsaicin are likely to be attributed to a non-specific, CGRP-independent mechanism.     

脑脊液中γ-干扰素检测对结核性脑膜炎的诊断价值

目的：探讨脑脊液（CSF）中γ-干扰素（IFN-γ）水平对结核性脑膜炎（TBM）的临床诊断价值。方法选取该院2013年5月至2014年2月收治的脑膜炎患者87例，分为TBM组（35例）和病毒性脑膜炎组（52例）。另选择同期在该院进行健康体检者60例为对照组。应用酶联免疫吸附试验（ELISA）方法对各组患者血清、CSF中及对照组人员血清中IFN-γ水平进行检测及比较分析。结果 TBM组患者CSF中IFN-γ水平[（486.0±35.0）ng/L]明显高于病毒性脑膜炎组[（94.0±40.0）ng/L]，差异有统计学意义（P＜0.01）；而 TBM 组患者血清 IFN-γ水平[（102.9±55.8）ng/L]与病毒性脑膜炎组[（87.9±36.2）ng/L]比较，差异无统计学意义（P＞0.05），但两组患者血清IFN-γ水平均高于对照组[（13.9±6.8）ng/L]，差异有统计学意义（P＜0.01）；TBM组患者CSF中INF-γ水平明显高于血清，差异有统计学意义（P＜0.01）。CSF中IFN-γ诊断TBM的敏感性及特异性分别为84.2%、96.5%。结论 CSF中IFN-γ水平检测对诊断TBM有较大辅助作用。     

当归总苯酞对大鼠脑缺血再灌注损伤的改善作用

目的研究当归总苯酞对脑缺血再灌注损伤的改善作用。方法 SD大鼠口服给予当归总苯酞0.05,0.1和0.2 g·kg-1,每日1次,连续7 d。第7天给药30 min后采用线栓法制备大鼠大脑中动脉阻断再灌注损伤模型,于再灌前、再灌2和24 h进行神经功能评分,计算脑梗死面积和脑水肿比例,检测丙二醛(MDA)含量和超氧化物歧化酶(SOD)活性。另同样给予药物处理的大鼠于第7天股静脉注射10%高分子右旋糖酐5 m.lkg-1,检测脑膜微循环血流量。结果与假手术组相比,模型组神经功能评分增高,脑梗死面积明显增加,出现脑水肿,MDA含量增加,同时SOD活性降低。与模型组比较,当归总苯酞0.1和0.2 g·kg-1组神经功能评分分别降低了20.4%和28.7%(P<0.05);再灌2 h当归总苯酞0.05,0.1和0.2 g·kg-1可使神经功能评分分别降低15.5%,28.7%和29.9%(P<0.01);再灌24 h则分别降低11.9%,25.3%和37.4%(P<0.01),脑梗死面积分别缩小9.8%,41.7%和49.6%(P<0.05);脑水肿程度分别减轻9%,42%和52%(P<0.01);同时使脑组织MDA含量降低,最大降低幅度为62.0%(P<0.01);SOD活性升高,最大升高幅度为77.1%(P<0.01)。与假手术组相比,模型组脑血流量明显减少;与模型组相比,给予当归总苯酞可使大鼠脑血流量出现不同程度的回升(P<0.05),但仍明显低于假手术组(P<0.05)。结论当归总苯酞对大鼠脑缺血再灌注损伤具有明显的改善作用。     

Neurovascular pharmacology of migraine

Migraine is a paroxysmal neurovascular disorder, which affects a significant proportion of the population. Since dilation of cranial blood vessels is likely to be responsible for the headache experienced in migraine, many experimental models for the study of migraine have focussed on this feature. The current review discusses a model that is based on the constriction of carotid arteriovenous anastomoses in anaesthetized pigs, which has during the last decades proven of great value in identifying potential antimigraine drugs acting via a vascular mechanism. Further, the use of human isolated blood vessels in migraine research is discussed. Thirdly, we describe an integrated neurovascular model, where dural vasodilatation in response to trigeminal perivascular nerve stimulation can be studied. Such a model not only allows an in-depth characterization of directly vascularly acting drugs, but also of drugs that are supposed to act via inhibition of vasodilator responses to endogenous neuropeptides, or of drugs that inhibit the release of these neuropeptides. We discuss the use of this model in a study on the influence of female sex hormones on migraine. Finally, the implementation of this model in mice is considered. Such a murine model allows the use of genetically modified animals, which will lead to a better understanding of the ion channel mutations that are found in migraine patients.     

5-HT7 receptor-mediated dilatation in the middle meningeal artery of anesthetized rats

Topical administration of 5-carboxamidotryptamine (5-CT; 0.01-1000 microM) to the exposed dura mater encephali of anesthetized rats produced decreases in blood pressure and dilatation in the middle meningeal artery. Pretreatment with the 5-HT(1B/1D) receptor antagonist, N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1-biphenyl]-4-carboxamide hydrochloride monohydrate (GR-127935; 1 mg/kg, i.v.), unmasked meningeal dilator responses to lower concentrations of 5-CT, and attenuated those to higher concentrations; GR-127935 also inhibited 5-CT-induced hypotension. The 5-HT7 receptor antagonist, (R)-1-{(3-hydroxyphenyl)sulfonyl}-2-{2-(2-(4-methyl-1-piperidinyl) ethyl} pyrrolidine (SB-269970; 1 mg/kg, i.v.), strongly inhibited dilator and hypotensive responses to 5-CT; the combination of GR-127935+SB-269970 (1 mg/kg, i.v., each) further inhibited meningeal and hypotensive responses. Thus, 5-CT may produce dilatation in the middle meningeal artery via 5-HT7 receptors; complex effects appear to involve 5-HT(1B/1D) receptors.     

Effects of current and prospective antimigraine drugs on the porcine isolated meningeal artery

Vasoconstriction to agonists at serotonin (5-hydroxytryptamine; 5-HT) receptors and α-adrenoceptors, as well as vasodilatation induced by α-CGRP, have been well described in the porcine carotid circulation in vivo. The present study sets out to investigate the effects of current and prospective antimigraine drugs on porcine meningeal artery segments in vitro. Sumatriptan, ergotamine, dihydroergotamine, isometheptene and clonidine failed to contract the meningeal artery, but 5-HT, noradrenaline and phenylephrine induced concentration-dependent contractions. The contractions to 5-HT were competitively antagonized by the 5-HT_2A receptor antagonist ketanserin, whilst those to noradrenaline were antagonized by α₁-(prazosin), α₂-(rauwolscine and yohimbine) and α_2C/2B-(OPC-28326) adrenoceptor antagonists. Whilst dobutamine and salbutamol were ineffective, α-CGRP produced concentration-dependent relaxations that were antagonized by the CGRP₁ receptor antagonist olcegepant. In agreement with their lack of contractile effect, sumatriptan and ergotamine failed to influence forskolin-stimulated cyclic AMP accumulation in the porcine meningeal artery; in contrast, both compounds decreased forskolin-stimulated cyclic AMP accumulation in the human isolated saphenous vein, where they induced contractions. Finally, using RT-PCR, we could demonstrate the presence of mRNAs encoding for several 5-HT receptors (5-HT_1B, 5-HT_1D, 5-HT_1F, 5-HT_2A and 5-HT₇) and adrenoceptors (α_1A, α_1B, α_1D, α_2A, α_2B, α_2C, β₁ and β₂), as well as that for the calcitonin receptor like receptor, a component of the CGRP₁ receptor. These results suggest that: (i) the porcine meningeal artery may not be involved in the vasoconstriction of the carotid vascular bed elicited by antimigraine drugs in anaesthetized pigs, and (ii) the mismatch between the presence of receptor mRNA and the lack of response to sumatriptan, dobutamine and salbutamol implies that mRNAs for the 5-HT_1B receptor and β₁- and β₂-adrenoceptors are probably unstable, or that their density is too low for being translated as receptor protein in sufficient quantities.     

Release of immunoreactive substance P in the brain stem upon stimulation of the cranial dura mater with low pH – inhibition by the serotonin (5-HT1) receptor agonist CP 93,129

1. The therapeutical benefit of serotonin (5-HT₁) receptor agonists in the treatment of migraine headache has been attributed to their inhibitory effect on the release of pro-inflammatory neuropeptides from trigeminal afferents within the cranial meninges. The effect of 5-HT₁ receptor agonists on the release of neuropeptides from central afferent terminals has not been examined so far. In the present study in the rat we therefore measured the effect of the 5-HT_1B receptor agonist CP 93,129 on the stimulation-evoked release of immunoreactive substance P (ir-SP) in the spinal trigeminal nucleus.
2. To measure release of ir-SP, microprobes coated with antibody to substance P were inserted into the medulla oblongata at the level of the obex. The ipsilateral parietal dura mater encephali was exposed and stimulated with acid phosphate buffered Tyrode solution (pH 5.8). This chemical stimulus increased the release of ir-SP in the medullary dorsal horn.
3. Systemic (i.v.) administration of CP 93,129 (460 nmol kg⁻¹) prior to stimulation suppressed the stimulation-evoked increase of release of ir-SP. Local administration of CP 93,129 (10 μM) to the dorsal surface of the medulla had no significant inhibitory effect on the release.
4. It is concluded that systemically applied 5-HT₁ receptor agonists reduce the stimulation-evoked release of substance P from the central endings of meningeal afferents in the spinal trigeminal nucleus (medullary dorsal horn). This inhibitory effect may contribute to the antinociceptive effect of 5-HT₁ receptor agonists in migraine.

     

Spinal Disposition and Meningeal Permeability of Local Anesthetics

PURPOSE: To investigate the spinal disposition, the cerebrospinal fluid (CSF) bioavailability, and the ex vivo meningeal permeability of six homologous pipecoloxylidide local anesthetics and to search for correlations with lipophilicity. METHODS: The ex vivo meningeal permeability was studied on fresh specimen of meninges (dura mater and arachnoid mater) removed from lumbar and cervical level of rabbit spine following laminectomy. Spinal disposition and CSF bioavailability were investigated using microdialysis sampling after simultaneous injection of an equimolar dose of the six homologs in the epidural or in the intrathecal spaces. In a first step, intrathecal and epidural microdialysis were performed after epidural administration. In a second step, intrathecal microdialysis was performed after intrathecal administration. RESULTS: Permeability through cervical and lumbar meninges was linearly correlated, and the cervical permeability was around 60% of the lumbar permeability. Apparent permeability data showed a parabolic relationship with the lipophilicity of the derivatives with a marked decrease in permeability for log P above 3. In vivo experiments have shown that the absorption rate constant linearly decreased with lipophilicity of the derivatives (0.171 to 0.125 min(-1)) whereas the intrathecal bioavailability, which was low, increased with lipophilicity (7.2 to 15.9%). CONCLUSIONS: The unexpected increase in CSF bioavailability with a decrease in absorption rate through meninges emphasizes the role of specific competitive clearance and distribution processes in the epidural space.     

Current Understanding of Central Nervous System Drainage Systems: Implications in the Context of Neurodegenerative Diseases

Until recently, it was thought that there were no lymphatic vessels in the central nervous system (CNS). Therefore, all metabolic processes were assumed to take place only in the circulation of the cerebrospinal fluid (CSF) and through the blood-brain barrier’s (BBB), which regulate ion transport and ensure the functioning of the CNS. However, recent findings yield a new perspective: There is an exchange of CSF with interstitial fluid (ISF), which is drained to the paravenous space and reaches lymphatic nodes at the end. This circulation is known as the glymphatic system. The glymphatic system is an extensive network of meningeal lymphatic vessels (MLV) in the basal area of the skull that provides another path for waste products from CNS to reach the bloodstream. MLV develop postnatally, initially appearing around the foramina in the basal part of the skull and the spinal cord, thereafter sprouting along the skull’s blood vessels and spinal nerves in various areas of the meninges. VEGF-C protein (vascular endothelial growth factor), expressed mainly by vascular smooth cells, plays an important role in the development of the MLV. The regenerative potential and plasticity of MLV and the novel discoveries related to CNS drainage offer potential for the treatment of neurodegenerative diseases such as dementia, hydrocephalus, stroke, multiple sclerosis, and Alzheimer disease (AD). Herein, we present an overview of the structure and function of the glymphatic system and MLV, and their potential involvement in the pathology and progression of neurodegenerative diseases.