The growth of the canine glioblastoma cell line D-GBM and the canine histiocytic sarcoma cell line DH82 is inhibited by the resveratrol oligomers hopeaphenol and r2-viniferin.

Vineatrol(®) 30 is a grapevine-shoot extract, which contains resveratrol as well as considerable amounts of so-called resveratrol oligomers such as hopeaphenol and r2-viniferin. In this study, we analysed whether the two above-mentioned resveratrol oligomers were able to inhibit the growth of the canine glioblastoma cell line D-GBM and the canine histiocytic sarcoma cell line DH82, compared their potency to inhibit tumour cell growth with that of resveratrol and determined whether the induction of apoptosis via caspase 9 and 3/7 activation underlies the tumour cell growth-inhibiting effect of hopeaphenol and r2-viniferin. Vineatrol(®) 30, resveratrol, hopeaphenol and r2-viniferin inhibited the growth of D-GBM and DH82 cells in a concentration-dependent manner, whereby hopeaphenol and r2-viniferin were more potent than resveratrol itself in inhibiting the growth of the canine tumour cell lines. Moreover, the anti-proliferative effect of both resveratrol oligomers in D-GBM cells is based on their capacity to induce caspase 9 and 3/7 activation.

Pericranial injection of botulinum toxin type A (Dysport) for tension-type headache - a multicentre, double-blind, randomized, placebo-controlled study.

Increasingly, botulinum type A toxin is used to influence pathologically increased muscle activity in conditions such as dystonia and spasticity. Studies have also assessed its efficacy in tension-type headache, where muscle tenderness may be increased. We undertook a prospective, multicentre, randomized, double-blind, placebo-controlled trial. Patients received injections of Dysport (total dose of 420 or 210 units) or saline placebo in 18 sites on the head and neck. Of 125 patients treated, 118 were included in the intention-to-treat dataset. No significant differences between each verum group and placebo were seen for the primary efficacy parameter - change in the number of headache-free days at 4-8 weeks after injection compared with 4 weeks before injection. The groups receiving 420 or 210 units of Dysport experienced 2.60 and 2.87 more headache-free days respectively, compared with 1.93 more headache-free days for the placebo group (P = 0.66 versus 420 units; P = 0.52 versus 210 units). Treatment with 420 units of Dysport was associated with significant improvements compared with placebo for two secondary efficacy parameters: mean change in headache duration from baseline to weeks 8-12 (P < 0.05) and improved global physician and patient assessment scores (P < 0.05). Further studies should address the possible value of multiple injections with extended observation periods, dose optimization, and whether duration of headache history and number of previous treatments are predictors of patient response.

[Primary headaches and the influence of inflammatory diseases of the CNS and their respective immunmodulatory therapy]. / Entzündliche Erkrankungen des ZNS sowie immunmodulatorische Therapie und ihr Einfluss auf primäre Kopfschmerzen.

Headaches are a well known symptom in systemic or local inflammatory diseases such as pneumonia or meningitis. These headaches may mimic primary headaches and are thought to be generated by inflammatory mediators acting directly on nociceptors or indirectly - via facilitation of neurons. Apart from prostaglandin and nitric oxide also cytokines (TNF-alpha or interleukin-6) may play a role. In primary headaches such as migraine inflammatory mechanisms also have been acclaimed to contribute to pain generation. The recently observed increase of migraine attacks under immunmodulatory therapy in multiple sclerosis has focussed attention on primary headaches in states of altered immunity, for instance in autoimmune disorders like lupus erythematosus, rheumatoid arthritis, or in patients treated with immunosuppressants. This article describes the standard of knowledge and tries to shed light on possible mechanisms of pain generation in the respective conditions.

Increased urinary excretion of nitric oxide metabolites in longitudinally monitored migraine patients.

This study evaluated a relationship between nitric oxide (NO) and migraine attacks in order to gain insight into migraine pathomechanism. The study groups consisted of 12 migraineurs and eight controls. All subjects collected morning urine samples for 40 consecutive days. Urinary NO metabolites, nitrite/nitrate (NO(x)) levels were measured with the vanadium-based assay, whilst creatinine (Cr) and neopterin were determined with high-performance liquid chromatography. The mean urinary NO(x)/Cr ratio and number of NO(x) peaks was significantly greater in the migraine group compared with controls (P = 0.01 and P = 0.007, respectively). In the second approach, high NO(x) values were re-assessed in relation to raised neopterin, a marker of systemic infection or inflammation, and were excluded. The excretion of NO(x) persisted being pulsatile, and migraineurs had more peaks compared with controls (P = 0.01). In seven patients, NO(x) peaks coincided with headache days. This was more frequent than expected by random association in four patients (Monte-Carlo simulation; odds ratios: 2.16-7.77; no overlap of 95% CI). In four patients, NO(x) peaks preceded or followed headache days. Although there is a difference in the pattern of urinary NO(x) excretion between control and migraine populations, the variable temporal association of NO(x) peaks and headaches suggests a complex role of NO in this condition.

Soluble interleukin-2 receptors increase during the active periods in cluster headache.

OBJECTIVE: To investigate whether cytokines are altered during the active period of cluster headache. BACKGROUND: Patients with cluster headache show activation of the hypothalamus in PET studies and via endocrinologic parameters. Data also suggest an inflammatory process occurs in cluster headache. A connection between the presumed inflammatory cause, an immunological activation, and the hypothalamus could be generated by certain cytokines. DESIGN AND METHODS: ELISA was used to determine the serum levels of soluble interleukin-2 receptors, interleukin-1, interleukin-6, and 2 soluble interleukin-6 receptors (sIL-6R and soluble gp130) in 18 patients with cluster headache (6 women and 12 men) during the cluster period and in 17 healthy controls who were headache-free (3 women and 14 men). RESULTS: Patients with cluster headache had significantly increased soluble interleukin-2 receptors (413.6+/-223 U/mL vs. 290.0+/-112 U/mL; P <.05) compared with controls. Serum levels of interleukin-1 (0.29+/-0.30 pg/mL vs. 0.13+/-0.13 pg/mL, n.s.), interleukin-6 (0.87+/-0.6 pg/mL vs. 0.91+/-0.7 pg/ml; n.s.), soluble interleukin-6 receptors (33,131+/-8,349 pg/mL vs. 35,063+/-7,606 pg/mL; n.s.), or soluble gp130 (289+/-59 pg/mL vs. 283+/-20 pg/mL; n.s.) did not differ between the 2 groups, although patients with cluster tended to have higher interleukin-1 values. CONCLUSIONS: Because elevated soluble interleukin-2 receptors indicate T cell activation, our findings suggest immune activation during cluster headache. Because interleukin-2 can activate the hypothalamus and stimulate the release of Corticotropin-releasing Factor (CRF), interleukin-2 could link a putative immunological cause of cluster headache with the observed hypothalamic activation. Systemic changes of interleukin-1 or the interleukin-6 system do not seem to play a role in cluster headache, as no alterations of serum levels were observed. Even so, unchanged serum levels do not exclude limited local production.

Decreased sTNF-RI in migraine patients?

Tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) have recently been found to have a pain-mediating function in addition to their immunological, proinflammatory function. According to the hypothesis of neurovascular inflammation in migraine, these two cytokines could contribute to migraine pain generation. We analysed IL-6 and its soluble receptors sIL-6R and sgp130 as well as TNF-alpha and its soluble receptor sTNF-RI in 27 migraine patients and eight headache-free controls. Migraine patients tended to have less sTNF-RI (794 +/- 158 pg/ml) than controls (945 +/- 137 pg/ml). No differences in cytokine concentrations were observed. If TNF-alpha plays a role in migraine physiopathology, migraine patients may lack sufficient antagonistic sTNF-RI to neutralize hyperalgesic TNF-alpha during a migraine attack.

[The immune system and primary headache syndromes]. / Immunsystem und primäre Kopfschmerzsyndrome.

The association between pain and inflammation and certain clinical signs led physicians to suspect a connection between immunological mechanisms and headache syndromes even years ago. This review intends to give an overview of the literature which deals with immunological mechanisms in headache syndromes--with divergent results. Thus, a food allergy as a cause of migraine only seems to be relevant in a few isolated cases. Immunoglobulins or infections do not seem to play a role. Whether the complement system, auto-antibodies, immune cells or cytokines are involved in migraine pathophysiology, still remains to be determined. With regards to cluster headache, a participation of the immune system seems more probable. Although a systemic vasculitis or auto-antibodies probably do not contribute to cluster headache pathophysiology, reports of an immune activation, especially of T-cells, predominate the literature. Nevertheless, the evidence for an immunogenically triggered cluster attack is still lacking. In summary, only a mutual modulation of the immune and the pain system can be assumed with certainty.

Dilated cervical epidural veins and extra arachnoid fluid collection in orthostatic headaches.

Cervical MRI of eight patients with severe orthostatic headache showed a convex-shaped, prominent, dilated anterior, internal vertebral venous plexus with a flow-void signal in all patients and in seven also extra arachnoid fluid collection. Follow-up MRI showed resolution of the abnormalities in all patients. The authors hypothesize that these findings reflect disturbed compensatory vascular mechanisms by which autoregulation of the CSF pressure tries to compensate for the reduced CSF volume.

TNF-alpha expression in painful and nonpainful neuropathies.

OBJECTIVE: To determine whether the cytokine tumor necrosis factor alpha (TNF-alpha) acts as a pain mediator in neuropathic pain in humans. BACKGROUND: In animal models, inflammatory cytokines such as TNF-alpha have been shown to facilitate neuropathic pain. METHODS: The expression of TNF-alpha was analyzed immunohistochemically in 20 human nerve biopsy specimens of patients with painful (n = 10) and nonpainful (n = 10) neuropathies. Additionally, serum soluble TNF-alpha receptor I (sTNF-RI) levels were determined in 24 patients with neuropathies, 16 of which were painful and 8 that were painless. RESULTS: Colocalization studies by confocal fluorescence microscopy for S-100 and TNF-alpha showed expression of TNF-alpha in human Schwann cells. Patients with painful neuropathies showed a stronger TNF-alpha immunoreactivity in myelinating Schwann cells relative to the epineurial background staining compared with patients with nonpainful neuropathy (0.949 +/- 0.047 vs 1.010 +/- 0.053, p < 0.05). Although there was no difference in sTNF-RI levels between painful (n = 16) and nonpainful (n = 8) neuropathies (sTNF-RI: 1412 +/- 545 pg/mL vs 1,318 +/- 175 pg/mL), patients with a mechanical allodynia (n = 9) had elevated serum sTNF-RI (1627 +/- 645 pg/mL vs 1233 +/- 192 pg/mL, p < 0.05) compared with patients without allodynia (n = 15). CONCLUSIONS: TNF-alpha expression of human Schwann cells may be up-regulated in painful neuropathies. The elevation of sTNF-RI in patients with centrally mediated mechanical allodynia suggests that systemic sTNF-RI levels may influence central pain processing mechanisms.

T-cell subsets and expression of integrins in peripheral blood of patients with migraine.

Neurogenic inflammation is considered as an animal model of human migraine attacks. Using flow cytometry, we examined T-cell subsets and their integrin expression in the peripheral blood of 32 migraine patients in order to evaluate a possible inflammatory process in humans, as postulated in the migraine animal model. Our results show that migraine patients have a significant increased proportion of T-helper (47.4 +/- 6.3% vs 43.2 +/- 5.8%; p < 0.01) and T-helper memory cells (23.6 +/- 5.9 vs 20.3 +/- 6.5%; p < 0.01). Moreover, the 22 migraine patients without aura also exhibited an increase of LFA-1 expression of T-helper cells (34.7 +/- 11.5%) compared to the 35 controls (27.5 +/- 12.0%; p < 0.01). These preliminary results support the hypothesis that immunological mechanisms (such as an enhanced lymphocyte endothelium interaction) could be part of the migraine pathophysiology in humans.

Neuroleptic treatment increases soluble IL-2 receptors and decreases soluble IL-6 receptors in schizophrenia.

The cytokines interleukin-2 (IL-2) and interleukin-6 (IL-6) increase during immune activation, they are released from activated astrocytes and microglial cells in the central nervous system (CNS), and they are able to enhance the catecholaminergic neurotransmission. This study focused on the soluble receptors of IL-2 and IL-6 (sIL-2R, sIL-6R) as a part of the regulation system of IL-2 and IL-6. We studied serum levels of sIL-2R in 30 schizophrenic patients not under neuroleptic medication during an acute exacerbation of the disease and reexamined these patients under neuroleptic treatment after clinical improvement. The sIL-6R levels of 39 schizophrenic patients were estimated under the same conditions. The results were compared with the levels of sIL-2R and sIL-6R in 42 healthy controls. No difference was found between the schizophrenic patients before neuroleptic treatment and the healthy controls. During neuroleptic treatment, however, there was a significant increase of sIL-2R levels and a significant decrease of the sIL-6R levels between the pre- and post-conditions. In comparison with healthy controls, the treatment group also showed increased sIL-2R levels and decreased sIL-6R levels. These results suggest that treatment with neuroleptics is associated with increased sIL-2R and decreased sIL-6R. Since sIL-2R bind and inactivate IL-2, whereas sIL-6R form an active complex with IL-6, the increase of sIL-2R and the decrease of sIL-6R together may reflect a functional down regulation of these activating cytokines. This suggests that neuroleptic therapy has a differentiated immunomodulatory effect.

Soluble IL-6 receptors in the serum and cerebrospinal fluid of paranoid schizophrenic patients.

Soluble Interleukin-6 receptor (sIL-6R) levels are strongly related to the levels of Interleukin-6 (IL-6), and sIL-6Rs increase the immune activating properties of IL-6. We estimated sIL-6R serum levels in 25 schizophrenic patients and 25 healthy controls. In the patients, SIL-6R-CSF levels were also measured. The psychopathology was rated according to the AMDP system. We found a significant correlation between serum and cerebrospinal fluid (CSF) levels of sIL-6R, suggesting that serum levels may be a meaningful marker for the central action of sIL-6R. Moreover, significant correlations between the paranoid-hallucinatory syndrome and sIL-6R levels both in serum and CSF were observed. This finding suggests that IL-6 plays a role in the paranoid-hallucinatory symptomatology in schizophrenia. This can be understood regarding the influence of IL-6 to the catecholaminergic neurotransmission. The downregulating effects of neuroleptic treatment to sIL-6R demonstrate that the sIL-6R levels are decreased in the whole group of schizophrenic patients compared to controls.