Peripheral Inflammatory Processes Research Articles

PIASγ Enhanced SUMO-2 Modification of Nurr1 Activation-Function-1 Domain Limits Nurr1 Transcriptional Synergy

Nurr1 (NR4A2) is a transcription factor that belongs to the orphan NR4A group of the nuclear receptor superfamily. Nurr1 plays key roles in the origin and maintenance of midbrain dopamine neurons, and peripheral inflammatory processes. PIASγ, a SUMO-E3 ligase, represses Nurr1 transcriptional activity. We report that Nurr1 is SUMOylated by SUMO-2 in the lysine 91 located in the transcriptional activation function 1 domain of Nurr1. Nurr1 SUMOylation by SUMO-2 is markedly facilitated by overexpressing wild type PIASγ, but not by a mutant form of PIASγ lacking its first LXXLL motif (PIASγmut1). This PIASγmut1 is also unable to interact with Nurr1 and to repress Nurr1 transcriptional activity. Interestingly, the mutant PIASγC342A that lacks SUMO ligase activity is still able to significantly repress Nurr1-dependent transcriptional activity, but not to enhance Nurr1 SUMOylation. A SUMOylation-deficient Nurr1 mutant displays higher transcriptional activity than the wild type Nurr1 only in promoters harboring more than one Nurr1 response element. Furthermore, lysine 91, the major target of Nurr1 SUMOylation is contained in a canonical synergy control motif, indicating that SUMO-2 posttranslational modification of Nurr1 regulates its transcriptional synergy in complex promoters. In conclusion, PIASγ can exert two types of negative regulations over Nurr1. On one hand, PIASγ limits Nurr1 transactivation in complex promoters by SUMOylating its lysine 91. On the other hand, PIASγ fully represses Nurr1 transactivation through a direct interaction, independently of its E3-ligase activity.

A possible correlation between oxytocin-induced and angiotensin IV-induced anti-hyperalgesia at the spinal level in rats

In our previous study, we showed that intrathecal (i.t.) administration of angiotensin IV (Ang IV), an insulin-regulated aminopeptidase (IRAP) inhibitor, attenuated inflammatory hyperalgesia in rats. Using the plantar test in rats with carrageenan-induced paw inflammation, we investigated the possible mechanism(s) of this effect. Because i.t. oxytocin was reported to produce a dose-dependent anti-hyperalgesia in rats with inflammation, we speculate that there is a possible correlation between oxytocin-induced and Ang IV-induced anti-hyperalgesia. Using i.t. co-administered atosiban (oxytocin receptor antagonist), the anti-hyperalgesia by Ang IV was completely abolished. This indicated that oxytocin could be the major IRAP substrate responsible for the anti-hyperalgesia by Ang IV. When Ang IV was co-administered with a low dose of oxytocin, there was a significant enhancing effect of Ang IV on oxytocin-induced anti-hyperalgesia. In recent reports, electrical stimulation on the paraventricular hypothalamic nucleus (PVN) was proved to increase oxytocin release at the spinal cord. Our results also showed that Ang IV could prolong the anti-hyperalgesia induced by PVN stimulation. This suggests a possible protective effect of Ang IV on endogenous oxytocin degradation/dysfunctioning. Moreover, we examined the local effect of intraplantarly injected Ang IV in the same model. Our results showed no effect of local Ang IV on hyperalgesia and paw edema, indicating that Ang IV may not regulate the peripheral inflammatory process. Overall, our study suggests that Ang IV may act through the inhibition of the activity of IRAP to reduce the degradation of oxytocin at the spinal cord, thereby leading to anti-hyperalgesia in rats with inflammation.

Solution Structures of the Prototypical 18 kDa Translocator Protein Ligand, PK 11195, Elucidated with 1H/13C NMR Spectroscopy and Quantum Chemistry

Eighteen kilodalton translocator protein (TSPO) is an important target for drug discovery and for clinical molecular imaging of brain and peripheral inflammatory processes. PK 11195 [1a; 1-(2-chlorophenyl)-N-methyl-(1-methylpropyl)-3-isoquinoline carboxamide] is the major prototypical high-affinity ligand for TSPO. Elucidation of the solution structure of 1a is of interest for understanding small-molecule ligand interactions with the lipophilic binding site of TSPO. Dynamic (1)H/(13)C NMR spectroscopy of 1a revealed four quite stable but interconverting rotamers, due to amide bond and 2-chlorophenyl group rotation. These rotamers have been neglected in previous descriptions of the structure of 1a and of the binding of 1a to TSPO. Here, we used quantum chemistry at the level of B3LYP/6-311+G(2d,p) to calculate (13)C and (1)H chemical shifts for the rotamers of 1a and for the very weak TSPO ligand, N-desmethyl-PK 11195 (1b). These data, plus experimental NMR data, were then used to characterize the structures of rotamers of 1a and 1b in organic solution. Energy barriers for both the amide bond and 2'-chlorophenyl group rotation of 1a were determined from dynamic (1)H NMR to be similar (ca.17 to 18 kcal/mol), and they compared well with those calculated at the level of B3LYP/6-31G*. Furthermore, the computed barrier for Z to E rotation is considerably lower in 1a(18.7 kcal/mol) than in 1b (25.4 kcal/mol). NMR (NOE) unequivocally demonstrated that the E rotamer of 1a is the more stable in solution by about 0.4 kcal/mol. These detailed structural findings will aid future TSPO ligand design and support the notion that TSPO prefers to bind ligands as amide E-rotamers.

Cognitive-Behavioral Stress Management Reverses Anxiety-Related Leukocyte Transcriptional Dynamics

Chronic threat and anxiety are associated with pro-inflammatory transcriptional profiles in circulating leukocytes, but the causal direction of that relationship has not been established. This study tested whether a cognitive-behavioral stress management (CBSM) intervention targeting negative affect and cognition might counteract anxiety-related transcriptional alterations in people confronting a major medical threat. One hundred ninety-nine women undergoing primary treatment of stage 0-III breast cancer were randomized to a 10-week CBSM protocol or an active control condition. Seventy-nine provided peripheral blood leukocyte samples for genome-wide transcriptional profiling and bioinformatic analyses at baseline, 6-month, and 12-month follow-ups. Baseline negative affect was associated with >50% differential expression of 201 leukocyte transcripts, including upregulated expression of pro-inflammatory and metastasis-related genes. CBSM altered leukocyte expression of 91 genes by >50% at follow-up (group × time interaction), including downregulation of pro-inflammatory and metastasis-related genes and upregulation of type I interferon response genes. Promoter-based bioinformatic analyses implicated decreased activity of NF-κB/Rel and GATA family transcription factors and increased activity of interferon response factors and the glucocorticoid receptor as potential mediators of CBSM-induced transcriptional alterations. In early-stage breast cancer patients, a 10-week CBSM intervention can reverse anxiety-related upregulation of pro-inflammatory gene expression in circulating leukocytes. These findings clarify the molecular signaling pathways by which behavioral interventions can influence physical health and alter peripheral inflammatory processes that may reciprocally affect brain affective and cognitive processes.

Postoperative delirium. Part 1

Delirium presents clinically with differing subtypes ranging from hyperactive to hypoactive. The clinical presentation is not clearly linked to specific pathophysiological mechanisms. Nevertheless, there seem to be different mechanisms that lead to delirium; for example the mechanisms leading to alcohol-withdrawal delirium are different from those responsible for postoperative delirium. In many forms of delirium, the brain's reaction to a peripheral inflammatory process is considered to be a pathophysiological key element and the aged brain seems to react more markedly to a peripheral inflammatory stimulus than a younger brain. The effects of inflammatory mediators on the brain include changes in neurotransmission and apoptosis. On a neurotransmitter level, impaired cholinergic transmission and disturbances of the intricate interactions between dopamine, serotonin and acetylcholine seem to play an important role in the development of delirium. The risk factors for delirium are categorised as predisposing or precipitating factors. In the presence of many predisposing factors, even trivial precipitating factors may trigger delirium, whereas in patients without or with only a few predisposing factors, a major precipitating insult is necessary to trigger delirium. Well documented predisposing factors are age, medical comorbidities, cognitive, functional, visual and hearing impairment and institutional residence. Important precipitating factors apart from surgery are admission to an ICU, anticholinergic drugs, alcohol or drug withdrawal, infections, iatrogenic complications, metabolic derangements and pain. Scores to predict the risk of delirium based on four or five risk factors have been validated in surgical patients.

Microsomal prostaglandin E synthase-1 is involved in the brain ischemic injury

Microsomal prostaglandin (PG) E synthase-1 (mPGES-1) is an inducible terminal enzyme in the synthetic pathway for PGE2, which has been demonstrated to participate in many peripheral pathological inflammatory processes. Recently, we demonstrated that mPGES-1 also has a role in brain inflammation, such as that following cerebral ischemia. The expressions of mPGES-1 and cyclooxygenase-2 (COX-2) were induced and co-localized in neurons, microglia and endothelial cells in the cerebral cortex after transient focal ischemia. Using mPGES-1 knockout (KO) mice in which the postischemic PGE2 production in the cortex was completely absent, we found that the ischemic injuries were reduced compared to those in wild-type (WT) mice. Furthermore, the ameliorated symptoms observed in KO mice after ischemia were reversed to almost the same severity as in WT mice by intracerebroventricular injection of PGE2 into KO mice, suggesting the involvement of mPGES-1 in the exaggeration of ischemic injury through PGE2 production. The induction and involvement of mPGES-1 in neurotoxicity were also observed in a glutamate-induced excitotoxicity model using rodent hippocampal slices. Glutamate increased the expression of mPGES-1 and production of PGE2. The protective effect of NS-398, an inhibitor of COX-2, on the excitotoxicity observed in WT slices was completely abolished in mPGES-1 KO slices, which showed less excitotoxicity than WT slices. In the transient focal ischemia model, injection of NS-398 reduced not only ischemic PGE2 production, but also ischemic injuries in WT mice, but not in mPGES-1 KO mice, which showed less dysfunction than WT mice. Our observations suggest that mPGES-1 is a critical determinant of postischemic neurological dysfunctions and that mPGES-1 and COX-2 are co-induced and co-localized by excess glutamate and act together to exacerbate stroke injury through excessive PGE2 production. Considering that COX-2 inhibitors may non-selectively suppress the production of many types of prostanoids that are essential for normal physiological function of the brain and that a large number of epidemiological studies have provided evidence of an increased cardiovascular risk associated with the use of COX-2, an mPGES-1 inhibitor may prove to be an injury-selective inhibitor with fewer side effects. Thus, the results from mPGES-1 KO mice suggest that mPGES-1 is a promising novel target for the treatment of human stroke.

Synthesis and biological evaluation of carbon-11- and fluorine-18-labeled 2-oxoquinoline derivatives for type 2 cannabinoid receptor positron emission tomography imaging

The type 2 cannabinoid (CB(2)) receptor is part of the endocannabinoid system and has been suggested as a mediator of several central and peripheral inflammatory processes. Imaging of the CB(2) receptor has been unsuccessful so far. We synthesized and evaluated a carbon-11- and a fluorine-18-labeled 2-oxoquinoline derivative as new PET tracers with high specificity and affinity for the CB(2) receptor. Two 2-oxoquinoline derivatives were synthesized and radiolabeled with either carbon-11 or fluorine-18. Their affinity and selectivity for the human CB(2) receptor were determined. Biological evaluation was done by biodistribution, radiometabolite and autoradiography studies in mice. In vitro studies showed that both compounds are high affinity CB(2)-specific inverse agonists. Biodistribution study of the tracers in mice showed a high in vivo initial brain uptake and fast brain washout, in accordance with the low CB(2) receptor expression levels in normal brain. A persistently high in vivo binding to the spleen was observed, which was inhibited by pretreatment with two structurally unrelated CB(2) selective inverse agonists. In vitro autoradiography studies with the radioligands confirmed CB(2)-specific binding to the mouse spleen. We synthesized two novel CB(2) receptor PET tracers that show high affinity/selectivity for CB(2) receptors. Both tracers show favourable characteristics as radioligands for central and peripheral in vivo visualization of the CB(2) receptor and are promising candidates for primate and human CB(2) PET imaging.

Cystitis is associated with TRPV1b-downregulation in rat dorsal root ganglia

The recently identified splice variant of the transient receptor vanilloid type 1 (TRPV1) molecule, TRPV1b, produces a negative-dominant effect on the responsiveness of the TRPV1 channel, which is increased by peripheral inflammatory processes. Here, we studied, using real-time polymerase chain reaction, whether cyclophosphamide injection-evoked cystitis is associated with altered TRPV1/TRPV1b expression in the L5-L6 dorsal root ganglia, which innervate the urinary bladder. We found that while TRPV1 mRNA expression was unchanged, the amount of TRPV1b transcript was significantly reduced in L5-L6 dorsal root ganglia during cystitis. These data indicate that peripheral inflammatory events induce changes in TRPV1b expression in primary sensory neurons, which may result in increased responsiveness of the TRPV1 channel.

Labelling and biological evaluation of [11C]methoxy-Sch225336: a radioligand for the cannabinoid-type 2 receptor

The cannabinoid type 2 receptor (CB(2) receptor) is part of the endocannabinoid system and has been suggested as mediator of a number of central and peripheral inflammatory processes. In the present study, we have synthesized N-[(1s)-1-[4-[[4-methoxy-2-[(4-[(11)C]methoxyphenyl)sulfonyl)-phenyl]sulfonyl] phenyl]ethyl]methanesulfonamide ([(11)C]methoxy-Sch225336) and evaluated this new tracer agent as a potential positron emission tomography radioligand for the in vivo visualization of CB(2) receptors. Sch225336 was demethylated and the resulting phenol precursor was radiolabelled with a carbon-11 methyl group by methylation using [(11)C]methyl iodide, followed by purification by high-performance liquid chromatography. The log P of [(11)C]methoxy-Sch225336 and its biodistribution in normal mice were determined. Enhancement of brain uptake by inhibition of blood-brain barrier (BBB) efflux transporters was studied. Mouse plasma was analysed to quantify the formation of radiometabolites. The affinity of Sch225336 for the human cannabinoid type 1 and type 2 receptor was determined. [(11)C]methoxy-Sch225336 was obtained with a decay corrected radiochemical yield of about 30% and a specific activity of 88.8 GBq/mumol (end of synthesis). After intravenous injection in mice, the compound is rapidly cleared from the blood through the hepatobiliary pathway and does not show particular retention in any of the major organs. Polar metabolites were found in mouse plasma. Brain uptake was low despite the favourable log P value of 2.15, which is partly due to efflux by BBB pumps. [(11)C]methoxy-Sch225336 is a good candidate for in vivo imaging of the CB(2) receptor, although the low blood-brain barrier penetration limits its potential for central nervous system imaging.

Inhaled Corticosteroids as Additional Treatment in Alpha-1-Antitrypsin-Deficiency-Related COPD

Background: No consistent data are available regarding the effect of inhaled corticosteroids (ICS) in α₁-antitrypsin-deficiency (AATD)-related COPD. Recent data report inflammatory effects of the polymers of α₁-antitrypsin on the peripheral lung. Objectives: The aim of this study was to assess the effectiveness of an extra-fine ICS, hydrofluoroalkane-134a beclometasone dipropionate (HFA-BDP) with a mass median aerodynamic diameter of 1.1 µm, on lung function and exercise tolerance in COPD patients with AATD when added to long-acting bronchodilators (LABAs). Methods: After a 1-week washout, 8 steroid-naïve COPD patients with AATD (ZZ genotype), within a double-blind randomized cross-over study, were assigned to one of the following 16-week treatments: (1) HFA-BDP 400 µg b.i.d., salmeterol 50 µg b.i.d. and oxitropium bromide 200 µg t.i.d. or (2) placebo, salmeterol 50 µg b.i.d. and oxitropium bromide 200 µg t.i.d; after a 2-week washout period they received the other treatment. In weeks 1, 17, 19 and 35, patients took a spirometry assessment (breathing air and heliox) and a shuttle walking test (SWT) with dyspnea assessed by the modified Borg scale. Results: Significant differences in improvement were found in FEV₁, FVC, IC, distance covered and dyspnea perceived during SWT between the 2 treatments and baseline values (p < 0.05; Friedman’s test). However, further analysis showed that only the LABAs + ICS condition showed significant increases in the FEV₁, FVC, IC, ΔMEF_50% and distance covered during SWT along with a reduction in maximum isostep exertional dyspnea (p < 0.05; Wilcoxon test). A greater distance was walked at the end of the SWT with LABA + ICS than LABAs alone (301 ± 105 vs. 270 ± 112 m; p < 0.05). Conclusions: In AATD-related COPD patients (ZZ genotype) the addition of extra-fine ICS to LABAs decreases airway narrowing, mostly in the small airways, further reducing dynamic hyperinflation with a marked improvement in exercise tolerance and dyspnea, suggesting that a peripheral inflammatory process contributes to airflow obstruction in these patients.

Acute ileal inflammatory cytokine response induced by irradiation is modulated by subdiaphragmatic vagotomy

Neural involvement plays a role in the genesis of the peripheral inflammatory process that contributes to the irradiation intestinal disorders. However, little is known about the role of vagus nerve in modulating inflammatory process in rat. Here, we have shown that the NF-κB activation was consistent with the acute overexpression of pro-inflammatory cytokines (IL- 1β, TNF-α, IL-6) at 3, 6, and 12 h induced by whole-body irradiation (8 Gy). Subdiaphragmatic vagotomy reduced NF-κB activation and cytokine transcription in the early period post-irradiation. In contrast, vagotomy amplified overexpression of irradiation-induced anti-cytokines (IL-10, IL-1Ra) and of receptors involved in anti-inflammatory effects (IL- 1RII, TNFRII). These results show that the vagus nerve is a pro-inflammatory pathway in early irradiation-induced intestinal inflammation.

Complex regional pain syndrome — 1: history, diagnostic criteria and etiology

Abstract Physical therapists and other health care providers frequently evaluate and treat patients with complex regional pain syndrome (CRPS). The term CRPS replaces the previous terms reflex sympathetic dystrophy (now referred to as CRPS Type I) and causalgia (CRPS Type II). Part 1 of this paper describes the diagnostic criteria for CRPS and the clinical features and etiology of both CRPS Types I and II. CRPS is a multifactorial syndrome with overlapping symptoms. Although much progress has been made in the understanding of CRPS, many questions remain unanswered. CRPS is probably a disease of the central nervous system. Yet, peripheral inflammatory processes, abnormal sympathetic-afferent coupling, and adrenoreceptor pathology may also be part of the picture. It is likely that in the near future the current concepts of CRPS will be replaced by a new mechanism-based term or group of terms leading to improved clinical guidelines. Part 2 in this series reviews the physical therapy management of patients with CRPS.

MULTIDISCIPLINARY PAIN ABSTRACTS: 31 . Neurology (31)

Complex regional pain syndrome (CRPS) is clinically characterized by sensory, autonomic and motor disturbances. Pathophysiologically there is evidence for functional changes within the central nervous system and for involvement of peripheral inflammatory processes. The sympathetic nervous system plays a key role in maintaining pain and autonomic dysfunction in the affected extremity. After a primary central lesion, secondary peripheral changes in the paretic extremity are suggested to be important in initiating a CRPS. Though there is no diagnostic gold standard, careful clinical evaluation and additional test procedures should lead to an adequate diagnosis. An early diagnosis and an interdisciplinary approach are important for optimal and successful treatment.

Recent trends in understanding and therapy of complex regional pain syndromes

Since the term "complex regional pain syndromes" (CRPS) was introduced based on a revised taxonomy for disorders previously called reflex sympathetic dystrophy and causalgia in 1995, much knowledge grew up on the understanding and therapy of the disease. This review gives an overview on the clinical characteristics, pathophysiology, diagnostic tools and therapeutic options in CRPS. It will especially focus on recent findings on the role of the sympathetic nervous system, the central nervous system and peripheral inflammatory processes as underlying mechanisms. Although there is no diagnostic gold standard, careful clinical evaluation and additional apparative test procedures are very helpful for the diagnosis. An early and interdisciplinary approach is the basis for an optimal and successful treatment.

Persistence of attacks of cluster headache after trigeminal nerve root section.

Brain. 2002;125(pt 5):976‐984.Cluster headache is a strictly unilateral headache that occurs in association with cranial autonomic features. We report a patient with a trigeminal nerve section who continued to have attacks. A 59‐year‐old man described a 14‐year history of left‐sided episodes of excruciating pain centred on the retro‐orbital and orbital regions. These episodes lasted 1‐4 h, recurring 2‐3 times daily. The attacks were associated with ipsilateral ptosis, conjunctival injection, lacrimation, rhinorrhoea and facial flushing. From 1986 to 1988, he had trials of medications without any benefit. In February 1988, he had complete surgical section of the left trigeminal sensory root that shortened the attacks in length for 1 month without change in their frequency or character. In April 1988, he had further surgical exploration and the root was found to be completely excised; post‐operatively, there was no change in the symptoms. From 1988 to 1999, he had a number of medications, including verapamil and indomethacin, all of which were ineffective. Prednisolone 30 mg orally daily rendered the patient completely pain free. Sumatriptan 100 mg orally and 6 mg subcutaneously aborted the attack after approximately 45 and 15 min, respectively. He was completely anaesthetic over the entire left trigeminal distribution. Left corneal reflex was absent. Motor function of the left trigeminal nerve was preserved. Neurological and physical examination was otherwise normal. MRI scan showed a marked reduction in the calibre of the left trigeminal nerve from the nerve root exit zone in the pons to Meckel's cave. An ECG‐gated three‐dimensional multislab MRI inflow angiogram was performed. No dilatation was observed in the left internal carotid artery during the cluster attack. Blink reflexes were elicited with a standard electrode and stimulus. Stimulation of the left supraorbital nerve produced neither ipsilateral nor contralateral blink reflex response. Stimulation of the right supraorbital nerve produced an ipsilateral response with a mean R2 onset latency of 36 ms and a contralateral response with a mean R2 onset latency of 32 ms. Lack of ipsilateral vessel dilatation makes the role of vascular factors in the initiation of cluster attacks questionable. With complete section of the left trigeminal sensory root the brain would perceive neither vasodilatation nor a peripheral neural inflammatory process; however, the patient continued to have an excellent response to sumatriptan. The case illustrates that cluster headache may be generated primarily from within the brain, and that triptans may have anti‐headache effects through an entirely central mechanism. Comment: A truly remarkable case. It has been said that a single case can make one rethink everything about a disorder. Dr. Goadsby's group has demonstrated a potential “cluster generator” in the hypothalamus. Now, with this case, they provide evidence that in a patient with no peripheral afferent information and no internal carotid artery changes, sumatriptan still works—evidence of its central effects in cluster. SJT The efficacy of oral sumatriptan in this patient raises the possibility of loss of blood‐brain barrier integrity. Might the surgical interventions have breached the BBB? It would be interesting to know whether a gadolinium MRI showed any evidence for this. DSM

Complex regional pain syndrome--diagnostic, mechanisms, CNS involvement and therapy.

Complex regional pain syndromes (CRPS, formerly reflex sympathetic dystrophy and causalgia) are neuropathic pain conditions of one extremity developing inadequately after a trauma. The initiating trauma affects primarily the extremity, but can also be a central lesion (e.g., spinal cord injury, stroke). CRPS is clinically characterized by sensory, autonomic and motor disturbances. Pathophysiologically there is evidence for functional changes within the central nervous system and for involvement of peripheral inflammatory processes. The sympathetic nervous system plays a key role in maintaining pain and autonomic dysfunction in the affected extremity. After a primary central lesion, secondary peripheral changes in the paretic extremity are suggested to be important in initiating a CRPS. Though there is no diagnostic gold standard, careful clinical evaluation and additional test procedures should lead to an adequate diagnosis. An early diagnosis and an interdisciplinary approach are important for optimal and successful treatment.

Inflammation and infection in clinical stroke.

Stroke has enormous clinical, social, and economic implications, and demands a significant effort from both basic and clinical science in the search for successful therapies. Atherosclerosis, the pathologic process underlying most coronary artery disease and the majority of ischemic stroke in humans, is an inflammatory process. Complex interactions occur between the classic risk factors for atherosclerosis and its clinical consequences. These interactions appear to involve inflammatory mechanisms both in the periphery and in the CNS. Central nervous system inflammation is important in the pathophysiologic processes occurring after the onset of cerebral ischemia in ischemic stroke, subarachnoid hemorrhage, and head injury. In addition, inflammation in the CNS or in the periphery may be a risk factor for the initial development of cerebral ischemia. Peripheral infection and inflammatory processes are likely to be important in this respect. Thus, it appears that inflammation may be important both before, in predisposing to a stroke, and afterwards, where it is important in the mechanisms of cerebral injury and repair. Inflammation is mediated by both molecular components, including cytokines, and cellular components, such as leukocytes and microglia, many of which possess pro- and/or antiinflammatory properties, with harmful or beneficial effects. Classic acute-phase reactants and body temperature are also modified in stroke, and may be useful in the prediction of events, outcome, and as therapeutic targets. New imaging techniques are important clinically because they facilitate dynamic evaluation of tissue damage in relation to outcome. Inflammatory conditions such as giant cell arteritis and systemic lupus erythematosus predispose to stroke, as do a range of acute and chronic infections, principally respiratory. Diverse mechanisms have been proposed to account for inflammation and infection-associated stroke, ranging from classic risk factors to disturbances of the immune and coagulation systems. Considerable opportunities therefore exist for the development of novel therapies. It seems likely that drugs currently used in the treatment of stroke, such as aspirin, statins, and modulators of the renin-angiotensin-aldosterone system, act at least partly via antiinflammatory mechanisms. Newer approaches have included antimicrobial and antileukocyte strategies. One of the most promising avenues may be the use of cytokine antagonism, for example, interleukin-1 receptor antagonist.

Increased nitric oxide release by transient peripheral noxious inputs to the spinal cord of rats: an in vivo voltammetric approach

Using in vivo voltammetric detection of nitric oxide (NO) a previous study demonstrated an increased NO release at the lumbar dorsal horn level of the spinal cord by peripheral inflammatory processes in decerebrated-spinalized rats. This study concerns the effects of acute peripheral stimulations. Gentle non-noxious or isolated nociceptive stimulation did not modify the oxidation current due to NO. However, transient transcutaneous repetitive electrical stimulation of the hindpaw at mild to high intensities (1, 3, and 6 mA) provoked increases in the voltammograms, which were prolonged after stimulation ceased. These effects were absent in animals pretreated with the N-methyl- d-aspartate channel blocker MK-801. The data provide novel direct evidence that NO participates, at least during repetitive stimulation, in the transmission of noxious afferent messages in the dorsal horn of the spinal cord.

Subcutaneous formalin and intraplantar carrageenan increase nitric oxide release as measured by in vivo voltammetry in the spinal cord

The paper describes in vivo voltammetric detection of nitric oxide with carbon fibre microelectrodes at the lumbar spinal dorsal horn level of decerebrated–spinalized rats during peripheral noxious inflammatory processes. At the lumbar (L3–L4) dorsal horn level, a nitric oxide dependent peak of oxidation current (650mV), remaining stable for up to 4h ((92±5)% of control) could be detected indicating that significant amounts of nitric oxide are produced continuously. Following subcutaneous injection in the hindpaw of 50μl of 0.5% formalin the oxidation current rapidly increased ((115±5)% of control at 25min) and reached (120±6)% of control 1h later. Subsequently the voltammograms stabilized for up to 90min and decreased ((107±4)% at 124min). After an injection in the hindpaw of 150μl of 4% carrageenan, the voltammograms remained at control level for 1h and then the oxidation current increased continuously for up to 4h ((145±16)% of control at 240min); such an increase was reversed by ketamine. In these two models of inflammation, the delay in onset and the duration of the increases in NO release within the dorsal horn relate, to some extent, to the time course of the peripheral inflammatory processes, since they are shorter after formalin than after carrageenan. The results provide a direct in vivo demonstration that the intercellular messenger nitric oxide participates in the transmission of noxious afferent messages within the dorsal horn of the spinal cord following peripheral inflammation.

Selective inhibition of cyclooxygenase-2 attenuates expression of inflammation-related genes in CNS injury.

Injury to the brain, whether arising from trauma, stroke, or infection, elicits a tissue response characterized by glial cell activation and production of inflammation-related gene products. A similar response occurs in Alzheimer’s disease, where deposits of amyloid-beta are associated with activated glia and a wide variety of inflammatory products have been detected (Neuroinflammation Working Group, 2000). The widespread use of glucocorticoids in spinal cord injury and epidemiological evidence that nonsteroidal anti-inflammatory drugs may be beneficial in Alzheimer’s disease indicate that therapies targeting inflammatory processes may be useful in treatment of central nervous system (CNS) injury and disease. Cyclooxygenase-2 (COX-2) plays a major role in peripheral inflammatory processes (Dubois et al., 1998). Tissue culture studies show that astrocytes and microglia have the capacity to express COX-2 in response to proinflammatory cytokines (O’Banion et al., 1996; O’Banion, 1999). However, little is known about the contribution of COX-2 to inflammatory processes in the CNS.KeywordsTraumatic Brain InjuryCentral Nervous System InjuryGlial ActivationTissue Culture StudyGlial Cell ActivationThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.