A new antioxidant compound H-290/51 modulates glutamate and GABA immunoreactivity in the rat spinal cord following trauma

Summary.  The involvement of the excitatory amino acid glutamate and the inhibitory amino acid gamma-amino butyric acid (GABA) in the pathophysiology of spinal cord injury is not known in details. This investigation is focused on the role of glutamate and GABA in a rat model of spinal cord trauma using immunohistochemistry. Spinal cord injury produced by a longitudinal incision of the right dorsal horn of the T10–11 segments resulted in profound edema and cell damage in the adjacent T9 segment at 5 h. Pretreatment with H-290/51 (50 mg/kg, p.o.), a potent antioxidant compound, effectively reduced the blood-spinal cord barrier (BSCB) permeability, edema formation and cell injury following trauma. At this time, untreated traumatised rats exhibited a marked increase in glutamate immunoreactivity along with a distinct decrease in GABA immunostaining in the T9 segment. These changes in glutamate and GABA immunoreactivity in traumatised rats were considerably attenuated by pretreatment with H-290/51. These results suggest that (i) oxidative stress contributes to alterations in glutamate and GABA in spinal cord injury, (ii) glutamate and GABA are important factors in the breakdown of the BSCB, edema formation and cell changes, and (iii) the antioxidant compound H-290/51 has a potential therapeutic value in the treatment of spinal cord injuries. Received July 3, 2001 Accepted August 6, 2001 Published online July 31, 2002     

Topical application of dynorphin A (1-17) antiserum attenuates trauma induced alterations in spinal cord evoked potentials,microvascular permeability disturbances,edema formation and cell injury: an experimental study in the rat using electrophysiological and morphological approaches

Summary.  Dynorphin is a neuropeptide that is present in high quantities in the dorsal horn of the spinal cord. The peptide is actively involved in pain processing pathways. However, its involvement in spinal cord injury is not well known. Alteration in dynorphin immunoreactivity occurs following a focal trauma to the rat spinal cord. Infusion of dynorphin into the intrathecal space of the cord results in ischemia, cell damage and abnormal motor function. Antibodies to dynorphin when injected into the intrathecal space of the spinal cord following trauma improve motor recovery, reduce edema and cell changes. However, influence of dynorphin on trauma induced alteration in spinal cord bioelectrical activity is still not known. Spinal cord evoked potentials (SCEP) are good indicator of spinal cord pathology following trauma. Therefore, in present investigation, influence of dynorphin antibodies on trauma induced changes in SCEP were examined in our rat model. In addition, spinal cord edema formation, microvascular permeability disturbances and cell injury were also investigated. Our results show that topical application of dynorphin antiserum (1 : 200) two min before injury markedly attenuated the SCEP changes immediately after injury. In the antiserum treated animals, a significant reduction in the microvascular permeability, edema formation and cell injury was observed in the traumatised spinal cord. These observations suggest that (i) dynorphin is involved in the altered bioelectrical activity of the spinal cord following trauma, (ii) the peptide actively participates in the pathophysiological processes of cell injury in the spinal cord trauma, and (iii) the dynorphin antiserum has potential therapeutic value for the treatment of spinal cord injuries. Received July 3, 2001 Accepted August 6, 2001 Published online July 31, 2002     

Growth hormone attenuates alterations in spinal cord evoked potentials and cell injury following trauma to the rat spinal cord

The influence of exogenous rat growth hormone on spinal cord injury induced alterations in spinal cord evoked potentials (SCEP) and edema formation was examined in a rat model. Repeated topical application of rat growth hormone (20microl of 1microg/ml solution) applied 30min before injury and at 0min (at the time of injury), 10min, 30min, 60min, 120min, 180min, and 240min, resulted in a marked preservation of SCEP amplitude after injury. In addition, the treated traumatised cord showed significantly less edema and cell changes. These observations suggest that growth hormone has the capacity to improve spinal cord conduction and attenuate edema formation and cell injury in the cord indicating a potential therapeutic implication of this peptide in spinal cord injuries.     

Tamoxifen attenuates inflammatory-mediated damage and improves functional outcome after spinal cord injury in rats

Tamoxifen has been found to be neuroprotective in both transient and permanent experimental ischemic stroke. However, it remains unknown whether this agent shows a similar beneficial effect after spinal cord injury (SCI), and what are its underlying mechanisms. In this study, we investigated the efficacy of tamoxifen treatment in attenuating SCI-induced pathology. Blood–spinal cord barrier (BSCB) permeability, tissue edema formation, microglial activation, neuronal cell death and myelin loss were determined in rats subjected to spinal cord contusion. The results showed that tamoxifen, administered at 30 min post-injury, significantly decreased interleukin-1β (IL-1β) production induced by microglial activation, alleviated the amount of Evans blue leakage and edema formation. In addition, tamoxifen treatment clearly reduced the number of apoptotic neurons post-SCI. The myelin loss and the increase in production of myelin-associated axonal growth inhibitors were also found to be significantly attenuated at day 3 post-injury. Furthermore, rats treated with tamoxifen scored much higher on the locomotor rating scale after SCI than did vehicle-treated rats, suggesting improved functional outcome after SCI. Together, these results demonstrate that tamoxifen provides neuroprotective effects for treatment of SCI-related pathology and disability, and is therefore a potential neuroprotectant for human spinal cord injury therapy.     

A neutrophil elastase inhibitor (ONO-5046) reduces neurologic damage after spinal cord injury in rats

In view of a cytoprotective effect of elastase inhibitor on chemokine-mediated tissue injury, we examined the neuroprotective effect of ONO-5046, a specific inhibitor of neutrophil elastase, in rats with spinal cord injury. Standardized spinal cord compression markedly increased cytokine-induced neutrophil chemo-attractant (CINC)-1 mRNA and protein. Their increases correlated with neurologic severity of injured rats. Immunohistochemically, CINC-1 protein was detected sequentially in vascular endothelial cells at 4 h, in perivascular neutrophils at 8 h, and in neutrophils infiltrating into cord substance at 12 h. Pretreatment with ONO-5046 (50 mg/kg) markedly ameliorated motor disturbance in injured rats, and reduced CINC-1 protein and mRNA expression. ONO-5046 also significantly reduced the increase of neutrophil accumulation or infiltration estimated by myeloperoxidase activity, and the extent of vascular permeability by Evans blue extravasation in the injured cord segment in comparison to control animals receiving vehicle. These results suggest that CINC-1 contributed to inflammation in rat spinal cord injury and ONO-5046 attenuated neurologic damage partly by blocking CINC-1 production of the chemoattractant, preventing neutrophil activation and vascular endothelial cell injury.     

Spinal cord evoked potentials and edema in the pathophysiology of rat spinal cord injury

Summary The possibility that nitric oxide is somehow involved in the early bioelectrical disturbances following spinal cord injury in relation to the later pathophysiology of the spinal cord was examined in a rat model of spinal cord trauma. A focal trauma to the rat spinal cord was produced by an incision of the right dorsal horn of the T 10–11 segments under urethane anaesthesia. The spinal cord evoked potentials (SCEP) were recorded using epidural electrodes placed over the T9 and T12 segments of the cord following supramaximal stimulation of the right tibial and sural nerves in the hind leg. Trauma to the spinal cord significantly attenuated the SCEP amplitude (about 60%) immediately after injury which persisted up to 1h. However, a significant increase in SCEP latency was seen at the end of 5h after trauma. These spinal cord segments exhibited profound upregulation of neuronal nitric oxide synthase (NOS) immunoreactivity, and the development of edema and cell injury. Pretreatment with a serotonin synthesis inhibitor drug p-chlorophenylalanine (p-CPA) or an anxiolytic drug diazepam significantly attenuated the decrease in SCEP amplitude, upregulation of NOS, edema and cell injury. On the other hand, no significant reduction in SCEP amplitude, NOS immunolabelling, edema or cell changes were seen after injury in rats pretreated with L-NAME. These observations suggest that nitric oxide is somehow involved in the early disturbances of SCEP and contribute to the later pathophysiology of spinal cord injury.     

Preventive Role of Magnesium on Skeletal Muscle Ischemia–Reperfusion Injury—an Experimental Study

The present study aims to explore whether Mg infusion has a preventive effect on ischemia–reperfusion injury in rats. A total of 20 Sprague-Dawley-type adult male rats were used. In group 1 (control), 0.9% isotonic solution was administered. In group 2 (experiment), magnesium sulfate (0.5 mg per 100 g) was administered. Ischemia was induced for 15 min for the two groups. Magnesium (Mg), interleukin 8 (IL-8), and malondialdehyde levels were analyzed in blood, while edema, neutrophil infiltration, eosinophilia, loss of striation, and nucleolization were evaluated in histopathological examination. Mg levels in the experiment group were higher than those in the control group after ischemia–reperfusion (p < 0.05). In the control group, postischemia and postreperfusion IL-8 values were higher than preoperative values (p < 0.05). As for eosinophilia and loss of striation values, these were higher in the experiment group after ischemia–reperfusion than the values in the control group (p < 0.05). Histopathologically, Mg infusion cannot prevent the tissue injury triggered in ischemia–reperfusion periods. Eosinophilia can be one of the major and earliest markers of ischemia–reperfusion injury.     

Optimization of the solubilization and renaturation of fish growth hormone produced by Escherichia coli

Growth hormone (GH) enhances the growth rate of aquacultured fish and shellfish, but it is difficult to extract native GH from fish pituitary glands. However, fish recombinant GH (rGH) can be efficiently synthesized by Escherichia coli cells, although it exists in denatured form in inclusion bodies (IB). We studied the solubilization of IB and the renaturation of rGH to help facilitate the production of a large amount of biologically active rGH. A 100-ml sample of rGH-producing E. coli produced 73.43 ± 5.47 mg IB (dry weight, n = 3) after 20 h induction by 1 mM isopropyl β-o-thiogalactopyranoside. Interestingly, if the bacteria were induced by 0.1 mM β-lactose, 95.3 ± 3.43 mg of IB was obtained. The optimal conditions for denaturation and renaturation of rGH were when IB were solubilized in 6 M guanidine hydrochloride and then dialysed against pH 10 dialysis buffer (50 mM ammonium bicarbonate and 2 mM EDTA) containing 100 mM l-arginine, 2 mM oxidized glutathione and 2 mM reduced glutathione for 24 h at 4 °C in a volume ratio of 3 to 500. At least 20% of the denaturated rGH in IB was renatured. Juvenile black sea bream injected with 0.05 μg/g resultant rGH once every 2 weeks exhibited significant increases (P < 0.05) in weight gain (84%) relative to fish in the control group over a 16-week period. This process is an economical and effective way to obtain an active form of rGH biosynthesized by a prokaryotic system. Received: 18 November 1996 / Received revision: 5 March 1997 / Accepted: 7 March 1997     

Coupling of c-fos expression in the spinal cord and amygdala induced by dorsal neck muscles fatigue

c-fos gene expression in the cervical spinal cord and amygdala was examined in anaesthetized rats following muscle fatigue caused by intermittent high-rate (100 s⁻¹) electrical stimulation of the dorsal neck muscles (m. trapezius and m. splenius). Fatigue-related increases in c-fos expression were observed on the stimulated muscle side in the cervical C2–C4 (layers 1, 3–5, 7 and 10) spinal segments, bilaterally in the lumbar L4–L6 (layer 1) segments and in contralateral central (Ce), medial (Me), and basomedial (BM) amygdaloid nuclei. A scarce number of staining cells were found within lateral and basolateral nuclei. The rostro-caudal extent of c-fos expression in the spinal cord supports functional coupling of the cervical and lumbar regions during the neck muscle fatigue development. The distinct c-fos expression in the Ce and Me amygdaloid nuclei suggests that they may contribute to mediating the neck muscle fatigue-related nociception, autonomic and behavioural responses.     

Protective effect of vitamin E on spinal cord injury by compression and concurrent lipid peroxidation

Studies were made on the influence of vitamin E on the effects of compression injury of the spinal cord associated with ischemia in rats. The motor disturbance induced by spinal cord injury was greatly reduced by vitamin E supplementation. After injury, the spinal cord evoked potentials showed greater recovery of both amplitude and latency in the vitamin E-supplemented group than in the control group. Spinal cord blood flow was promptly restored and remained normal after injury in the vitamin E-supplemented group, but was significantly decreased from 3 h after injury in the control group. Thiobarbituric acid (TBA)—reactive substances in the spinal cord was immediately increased by compression injury in both groups, and after injury it persisted at a high value for 24 h in the control group, but decreased within 1 h in the vitamin E-supplemented group. Pathological examination of the spinal cord showed less damage, such as bleeding and edema, in the vitamin E-supplemented group than in the control group. Vitamin E may have protective effects on the spinal cord by inhibiting damage induced by lipid peroxidation and/or by sustaining the blood flow by maintaining the normal metabolism of arachidonic acid.     

Corticotropin-releasing factor (CRF) expression in postnatal and adult rat sacral parasympathetic nucleus (SPN)

The neural control of micturition undergoes marked changes during the early postnatal development. During the first few postnatal weeks, the spinal micturition reflex is gradually replaced by a spinobulbospinal reflex pathway that is responsible for micturition in adult animals. Upregulation of brainstem regulation of spinal micturition pathways may contribute to development of mature voiding patterns. We examined the expression of corticotropin-releasing factor (CRF), present in descending projections from Barrington's nucleus to the sacral parasympathetic nucleus (SPN), in postnatal (P0–P36) and adult Wistar rats (P60–90). CRF-immunoreactivity (IR) was present predominantly in the SPN region, although some staining was also observed in the dorsal horn and dorsal commissure in L5–S1 spinal segments. CRF-IR in spinal cord regions was age dependent (R ²=0.87–0.98). The majority of the CRF-IR in the lumbosacral spinal cord was eliminated by complete spinalization (2–3 weeks). Double-label immunohistochemistry was combined with quantitative confocal laser scanning microscopy to quantify the number and percentage of colocalization between CRF-immunoreactive varicosities and preganglionic somas or proximal neurites in the SPN in postnatal and adult rats. Results demonstrate an age-dependent upregulation of CRF-IR in the SPN region and specifically in association with preganglionic parasympathetic neurons identified with neuronal nitric oxide synthase (nNOS)-IR. CRF-immunoreactive varicosities on or within a 1 μm perimeter of nNOS-immunoreactive somas or proximal neurites also increased with postnatal age. The upregulation of CRF-IR in bulbospinal projections to the SPN may contribute to mature voiding reflexes. This work was supported in part through NIH grants DK051369, DK060481, DK065989, NS040796.     

The regenerative effects of electromagnetic field on spinal cord injury

Traumatic spinal cord injury (SCI) is typically the result of direct mechanical impact to the spine, leading to fracture and/or dislocation of the vertebrae along with damage to the surrounding soft tissues. Injury to the spinal cord results in disruption of axonal transmission of signals. This primary trauma causes secondary injuries that produce immunological responses such as neuroinflammation, which perpetuates neurodegeneration and cytotoxicity within the injured spinal cord. To date there is no FDA-approved pharmacological agent to prevent the development of secondary SCI and induce regenerative processes aimed at healing the spinal cord and restoring neurological function. An alternative method to electrically activate spinal circuits is the application of a noninvasive electromagnetic field (EMF) over intact vertebrae. The EMF method of modulating molecular signaling of inflammatory cells emitted in the extra-low frequency range of <100 Hz, and field strengths of <5 mT, has been reported to decrease inflammatory markers in macrophages, and increase endogenous mesenchymal stem cell (MSC) proliferation and differentiation rates. EMF has been reported to promote osteogenesis by improving the effects of osteogenic media, and increasing the proliferation of osteoblasts, while inhibiting osteoclast formation and increasing bone matrix in vitro. EMF has also been shown to increase chondrogenic markers and collagen and induce neural differentiation, while increasing cell viability by over 50%. As advances are made in stem cell technologies, stabilizing the cell line after differentiation is crucial to SCI repair. Once cell-seeded scaffolds are implanted, EMF may be applied outside the wound for potential continued adjunct treatment during recovery.     

The Correlation Among the Dynamic Change of Zn<Superscript>2+</Superscript>, ZnT-1, and Brain-Derived Neurotrophic Factor After Acute Spinal Cord Injury in Rats

Zinc plays an important role in regulating the expression of brain-derived neurotrophic factor (BDNF) and its receptor in nervous system, but the correlation among Zn²⁺, zinc transporter, and BDNF in spinal cord injuries (SCI) is not fully understood. The purpose of this study was to investigate the expression of Zn²⁺, zinc transporter 1 (ZnT-1), and BDNF, as well as their correlation in spinal cord-injured rats. One hundred Wistar male rats were divided into two groups: sham-operated group (as control group) and model group. Spinal cord injury was induced in model groups by hemisection of T9 on the left side. Compared with the control group, the serum zinc levels in SCI model group were significantly decreased after surgery, but zinc concentrations in spinal cord were increased gradually. The mRNA levels of ZnT-1 and BDNF were significantly increased in SCI model group, and there is a positive correlation between them (Spearman rho = 0.381, P = 0.0204). The correlation found between BDNF and ZnT-1 allows us to speculate that these two factors may be physiologically co-regulated, which may provide an idea for the treatment of SCI.     

bFGF通过抑制Nogo-A信号减少脊髓损伤后胶质瘢痕形成

脊髓损伤后胶质瘢痕的形成是阻碍神经恢复的关键原因之一。碱性成纤维细胞生长因子（basic fibroblast growth factor,bFGF）具有良好的神经保护及促进脊髓损伤的修复作用,然而其对于胶质瘢痕的影响及其机制仍不清楚。本研究通过采用血管动脉夹（30 g）夹闭雌性SD大鼠脊髓2 min造成急性脊髓损伤模型并予以每天皮下注射bFGF（80 μg/kg）,探讨bFGF促进脊髓损伤的恢复作用是否涉及到胶质瘢痕调控和Nogo-A/NgR信号的相关机制。通过检测损伤后28 d,各组BBB评分和斜板试验,发现bFGF显著促进脊髓损伤后大鼠运动功能的恢复。HE及尼氏染色显示,bFGF处理组相对于生理盐水处理组,其神经元明显增多,空洞面积减少。同时,星形胶质细胞标记物GFAP免疫荧光结果表明,bFGF减少胶质瘢痕形成,抑制星形胶质细胞过度激活。同样,通过Western 印迹检测发现,bFGF处理后,胶质瘢痕相关蛋白（如GFAP, neurocan）以及神经突生长抑制蛋白（Nogo-A）信号通路相关蛋白质表达量下降。上述结果表明,bFGF可能通过抑制Nogo-A信号蛋白的表达,从而抑制胶质瘢痕的形成,促进脊髓损伤的恢复。此机制研究为脊髓损伤的治疗和恢复提供全新的思路和药物靶点。     

Changes in galanin immunoreactivity in rat micturition reflex pathways after cyclophosphamide-induced cystitis

Alterations in the expression of the neuropeptide, galanin, were examined in micturition reflex pathways of rat after cyclophosphamide (CYP)-induced cystitis of variable duration: acute (4 h), intermediate (48 h), or chronic (10 days). In control animals, galanin expression was present in specific regions of the gray matter in the rostral lumbar and caudal lumbosacral spinal cord, including: (1) the dorsal commissure (DCM); (2) superficial dorsal horn; (3) the regions of the intermediolateral cell column (L1–L2) and the sacral parasympathetic nucleus (SPN, L6–S1); and (4) the lateral collateral pathway (LCP) in lumbosacral spinal segments. Densitometry analysis demonstrated significant decreases (P≤0.01) in galanin immunoreactivity (IR) in these regions of the L1–S1 spinal cord after acute or intermediate CYP-induced cystitis. In contrast, increases (P≤0.01) in galanin–IR were observed in the DCM, SPN, or LCP regions in the L6–S1 spinal segments in rats with chronic cystitis. No changes in the number of galanin–immunoreactive cells were observed in the L1–S1 dorsal root ganglia (DRG) after CYP-induced cystitis of any duration. A small percentage of bladder afferent cells (Fast-blue-labeled) in the DRG expressed galanin–IR in control rats; this was not altered with cystitis. Galanin–IR was observed encircling DRG cells after chronic cystitis. These changes may contribute to urinary bladder dysfunction, altered sensation, and referred somatic hyperalgesia after cystitis.This work was supported in part through NIH grants DK051369, DK060481, DK065989, and NS040796.     

Increased expression of CDK11p58 and cyclin D3 following spinal cord injury in rats

Protein kinases are critical signalling molecules for normal cell growth and development. CDK11^p58 is a p34^cdc2-related protein kinase, and plays an important role in normal cell cycle progression. However its distribution and function in the central nervous system (CNS) lesion remain unclear. In this study, we mainly investigated the protein expression and cellular localization of CDK11 during spinal cord injury (SCI). Western blot analysis revealed that CDK11^p58 was not detected in normal spinal cord. It gradually increased, reached a peak at 3 day after SCI, and then decreased. The protein expression of CDK11^p58 was further analyzed by immunohistochemistry. The variable immunostaining patterns of CDK11^p58 were visualized at different periods of injury. Double immunofluorescence staining showed that CDK11 was co-expressed with NeuN, CNPase and GFAP. Co-localization of CDK11/active caspase-3 and CDK11/proliferating cell nuclear antigen (PCNA) were detected in some cells. Cyclin D3, which was associated with CDK11^p58 and could enhance kinase activity, was detected in the normal and injured spinal cord. The cyclin D3 protein underwent a similar pattern with CDK11^p58 during SCI. Double immunofluorescence staining indicated that CDK11 co-expressed with cyclin D3 in neurons and glial cells. Coimmunoprecipitation further showed that CDK11^p58 and cyclin D3 interacted with each other in the damaged spinal cord. Thus, it is likely CDK11^p58 and cyclin D3 could interact with each other after acute SCI. Another partner of CDK11^p58 was β-1,4-galactosyltransferase 1 (β-1,4-GT 1). The co-localization of CDK11/β-1,4-GT 1 in the damaged spinal cord was revealed by immunofluorescence analysis. The cyclin D3-CDK4 complexes were also present by coimmunoprecipitation analysis. Taken together, these data suggested that both CDK11 and cyclin D3 may play important roles in spinal cord pathophysiology. The authors Yuhong Ji and Feng Xiao contributed equally to this work.     

The Selenium Levels of Mothers and Their Neonates Using Hair,Breast Milk,Meconium, and Maternal and Umbilical Cord Blood in Van Basin

The objective of the present study is to calculate linear regressions between a mother and her child with respect to their selenium concentration (ng/g) in the following traits: maternal blood and umbilical cord blood, maternal and child hair, maternal milk and child umbilical cord blood, maternal milk and meconium, maternal blood plasma, and child meconium. The data were collected at Research Hospital of the University of Yüzüncü Yıl from 30 pairs of mothers and their newborn baby. The mean maternal serum Se level in 30 mothers was 68.52 ± 3.57 ng/g and cord plasma level was 119.90 ± 18.08 ng/g. The Se concentration in maternal and neonatal hair was 330.84 ± 39.03 and 1,124.76 ± 186.84 ng/g, respectively. The Se concentration of maternal milk at day 14 after delivery was determined as 68.63 ± 7.78 ng/g (n = 13) and the concentration of Se was 418.90 ± 45.49 ng/g (n = 22) for meconium of neonatal. There was no significant difference between maternal blood and milk Se levels. However, hair Se concentration was significantly higher than milk and maternal blood Se level. For each trait comparison, the average absolute difference in log₁₀-transformed Se concentration was calculated between a mother and her child. The observed average absolute difference was compared with a test distribution of 1,000 resampled bootstrap averages where the number of samples was maintained but the relationship between a mother and her child was randomized among samples (α = 0.05).     

Neuropeptides in spinal cord injury: Comparative experimental models

The possible role of endogenous opioids in the pathophysiology of spinal cord injury was evaluated utilizing a variety of experimental models and species. In the cat, we have shown that β-endorphin-like immunoreactivity was increased in plasma following traumatic spinal injury; such injury was associated with a decrease in spinal cord blood flow (SCBF) which was reversed by the opiate receptor antagonist naloxone. Naloxone treatment also significantly improved functional neurological recovery after severe injury. Thyrotropin-releasing hormone (TRH), possibly through its “anti-endorphin” actions, was even more effective than naloxone in improving functional recovery in the cat. In a rat model, utilizing a similar trauma method, TRH proved superior to naloxone in improving SCBF after injury. In addition, naloxone at high doses attenuated the hindlimb paralysis produced by temporary aortic occlusion in the rabbit. The high doses of naloxone required to improve neurological function after spinal injury suggest that naloxone's actions, if opiate receptor mediated, may be mediated by non-μ receptors. Dynorphin, an endogenous opioid with a high affinity for the κ receptor, produced hindlimb paralysis following intrathecal administration in rats. Taken together, these findings suggest that endogenous opioids, possibly acting at κ receptors in the spinal cord, may serve as pathophysiological factors in spinal cord injury.     

Effects of bradykinin in the cerebral circulation

All components of an intracerebral kallikrein-kinin system have been described. Thus, bradykinin (BK) acting from the parenchymal side as well as from the blood side may influence cerebral microcirculation. BK is a potent dilator of extra- and intraparenchymal cerebral arteries when acting from the perivascular side. The vasomotor effect of BK is mediated by B2 receptors which appear to be located at the abluminal membrane of the endothelial cell. Signal transmission from the endothelial to the smooth muscle cell is mediated by NO, prostanoids, free radicals or H2O2 depending on the animal species and on the location of the artery. Selective opening of the blood-brain barrier for small tracers (Na+-fluorescein: MW, 376) has been found in cats during cortical superfusion or intraarterial application of BK. This leakage is mediated by B2 receptors located at the luminal and abluminal membrane of the endothelial cells and probably mediated by an opening of tight junctions. Formation of brain edema has been found after ventriculo-cisternal perfusion or interstitial infusion of BK. This can be explained by increase of vascular permeability and cerebral blood flow due to arterial dilatation thus enhancing driving forces for the extravasation. An increase of the BK concentration in the interstitial space of the brain up to concentrations which induce extravasation, dilatation and edema formation has been found under several pathological conditions. Thus, BK may be involved in edema and necrosis formation after cold lesion, concussive brain injury, traumatic spinal cord and ischemic brain injury.