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Heparin and cancer revisited
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athritis, in conjunction with previous reports that iNOS knockout mice are more susceptible to experimentally induced arthropathies, suggests a possible protective role for iNOS in the context of joint inflammation.
TRENDS in Pharmacological Sciences Vol.22 No.5 May 2001
1 McCartney-Francis, N.L. et al. (2001) Selective inhibition of inducible nitric oxide synthase exacerbates erosive joint disease. J. Immunol. 166, 2734–2740
Rebecca Lever [email protected]
Antinociceptive and pro-inflammatory roles for NPY Y1 receptors Neuropetide Y (NPY) is a 36-amino-acid neuropeptide that is widely distributed in the CNS and PNS, where it is stored along with noradrenaline in sympathetic postganglionic fibres, and is also expressed in other autonomic (possibly parasympathetic) and sensory neurones. The physiological effects of NPY are mediated by at least six receptors (Y1–6), showing variable expression among mammalian species. An inhibitory modulation by NPY on the release of substance P (SP) from capsaicin-sensitive primary afferent neurones, from both central and peripheral nerve endings, was confirmed in many experimental conditions. Therefore, until recently, there was a general consensus that NPY had a putative antiinflammatory effect at the peripheral level and an antinociceptive effect in the CNS. Y1, Y2 and possibly other NPY receptors are expressed by dorsal root ganglion neurones. The recent availability of Y1 receptor knockout (Y1–/–) mice was expected to elucidate whether this receptor is involved in the inhibitory effect of NPY on neurogenic inflammation and nociception. Naveilhan and colleagues1 showed that –/– Y1 mice displayed a hyperalgesic phenotype in tests of thermal (hot plate and tail flick), chemical (first phase of formalin test, acetic-acid- and magnesium-sulfateinduced writhings), mechanical (Von Frey hairs) and neuropathic (partial nerve injury) nociception, and the antinociceptive effect observed following the intrathecal administration of NPY in wild-type animals was not evident in Y1–/– mice. Concomitantly, however, the capsaicin-induced, SPmediated pro-inflammatory effects were blunted in Y1–/– mice. In fact, the administration of capsaicin in a paw did not induce plasma extravasation and oedema in Y1–/– mice, and the effects of mustard oil were also attenuated. By contrast, neither the inflammatory responses induced by carrageenan nor those induced by SP were modified in Y1–/– animals. Furthermore, the pro-inflammatory effects of capsaicin in
wild-type mice were mimicked by a Y1 receptor agonist and were prevented by the selective Y1 receptor antagonist BIBP3226. In Y1–/– mice, tissue concentrations of SP were comparable with those found in normal mice, but capsaicin failed to induce SP release and subsequent neuropeptide depletion. …an opposing role of Y1 and Y2 receptors ‘… (or other Y receptors) in the excitability of capsaicin-sensitive nerve terminals could exist if both receptors are tonically stimulated by endogenous NPY.’ These results led the authors to conclude that Y1 receptors exert a tonic physiological role in reducing nociceptive inputs at the spinal cord level, whereas at the peripheral level, the stimulation of these receptors is both necessary and sufficient for triggering neurogenic inflammation. An alternative hypothesis could reconcile previous and present findings on the role of NPY and NPY receptors in neurogenic inflammation: an opposing role of Y1 and Y2 receptors (or other Y receptors) in the excitability of capsaicin-sensitive nerve terminals could exist if both receptors are tonically stimulated by endogenous NPY. In wild-type animals, the exogenous administration of NPY has an inhibitory effect on capsaicininduced inflammatory responses, possibly because of a preferential stimulation of Y2 receptors. In Y1–/– animals, endogenous NPY could be sufficient for the inhibition of the excitability of capsaicin-sensitive nerve terminals through the stimulation of Y2 receptors. This hypothesis could be tested either through the construction of Y2–/– mice, or with the use of already available selective Y2 receptor antagonists. 1 Naveilhan, P. et al. (2001) Reduced antinociception and plasma protein extravasation in mice lacking a neuropeptide Y receptor. Nature 409, 513–517
Alessandro Lecci [email protected]
221
In Brief
Heparin and cancer revisited The notion that the common anticoagulant heparin could be used to stem the spread of cancer is not new. It has long been known that the drug, administered intravenously, can inhibit tumour metastasis. But heparin therapy can be difficult to manage on an outpatient basis, and the subject fell out of favour when oral anticoagulants were found to have little or no anti-metastatic effect. Now, Lubor Borsig and co-workers hope that their findings (Proc. Natl. Acad. Sci. U. S. A. 2001, Vol. 98, pp. 3352–3357) will put heparin therapy for metastasis prevention back on the clinical agenda. The group confirmed that heparin’s antimetastatic action is not due to its ability to prevent blood clotting; instead, they found that the drug blocks metastatic progression by inhibiting P-selectin-based platelet interactions with tumour cell-surface mucins. Stripped of their ‘platelet cloak’, tumour cells were left open to attack by macrophages. A single dose of heparin, which blocked early platelet–tumour-cell interactions, was sufficient to prevent longterm organ colonization. The authors suggest that heparin treatment be explored with a new mechanistic paradigm in mind. RC
Disappointment for Parkinson’s disease patients The first controlled trials of foetal transplants of dopamine-containing neurones in patients with severe Parkinson’s disease have ended in disappointment. Curt Freed and colleagues (New Engl. J. Med. 2001, Vol. 344, pp. 710–719) showed that fibre outgrowth from neurones implanted in the putamen occurred in the majority of cases. However, the treatment, previously hailed as a potential cure for the disorder, was found to improve symptoms only in younger patients. Subjects over 60 years of age – which represent the majority of those suffering from Parkinson’s disease – did not appear to benefit. Moreover, 15% of patients developed dystonia and dyskinesias after improvement in the first year; these distressing developments were ascribed to an excess of dopamine. Levodopa and other dopaminergic drugs remain the principal treatment for Parkinson’s disease patients. RC
http://tips.trends.com 0165-6147/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.
athritis, in conjunction with previous reports that iNOS knockout mice are more susceptible to experimentally induced arthropathies, suggests a possible protective role for iNOS in the context of joint inflammation.
TRENDS in Pharmacological Sciences Vol.22 No.5 May 2001
1 McCartney-Francis, N.L. et al. (2001) Selective inhibition of inducible nitric oxide synthase exacerbates erosive joint disease. J. Immunol. 166, 2734–2740
Rebecca Lever [email protected]
Antinociceptive and pro-inflammatory roles for NPY Y1 receptors Neuropetide Y (NPY) is a 36-amino-acid neuropeptide that is widely distributed in the CNS and PNS, where it is stored along with noradrenaline in sympathetic postganglionic fibres, and is also expressed in other autonomic (possibly parasympathetic) and sensory neurones. The physiological effects of NPY are mediated by at least six receptors (Y1–6), showing variable expression among mammalian species. An inhibitory modulation by NPY on the release of substance P (SP) from capsaicin-sensitive primary afferent neurones, from both central and peripheral nerve endings, was confirmed in many experimental conditions. Therefore, until recently, there was a general consensus that NPY had a putative antiinflammatory effect at the peripheral level and an antinociceptive effect in the CNS. Y1, Y2 and possibly other NPY receptors are expressed by dorsal root ganglion neurones. The recent availability of Y1 receptor knockout (Y1–/–) mice was expected to elucidate whether this receptor is involved in the inhibitory effect of NPY on neurogenic inflammation and nociception. Naveilhan and colleagues1 showed that –/– Y1 mice displayed a hyperalgesic phenotype in tests of thermal (hot plate and tail flick), chemical (first phase of formalin test, acetic-acid- and magnesium-sulfateinduced writhings), mechanical (Von Frey hairs) and neuropathic (partial nerve injury) nociception, and the antinociceptive effect observed following the intrathecal administration of NPY in wild-type animals was not evident in Y1–/– mice. Concomitantly, however, the capsaicin-induced, SPmediated pro-inflammatory effects were blunted in Y1–/– mice. In fact, the administration of capsaicin in a paw did not induce plasma extravasation and oedema in Y1–/– mice, and the effects of mustard oil were also attenuated. By contrast, neither the inflammatory responses induced by carrageenan nor those induced by SP were modified in Y1–/– animals. Furthermore, the pro-inflammatory effects of capsaicin in
wild-type mice were mimicked by a Y1 receptor agonist and were prevented by the selective Y1 receptor antagonist BIBP3226. In Y1–/– mice, tissue concentrations of SP were comparable with those found in normal mice, but capsaicin failed to induce SP release and subsequent neuropeptide depletion. …an opposing role of Y1 and Y2 receptors ‘… (or other Y receptors) in the excitability of capsaicin-sensitive nerve terminals could exist if both receptors are tonically stimulated by endogenous NPY.’ These results led the authors to conclude that Y1 receptors exert a tonic physiological role in reducing nociceptive inputs at the spinal cord level, whereas at the peripheral level, the stimulation of these receptors is both necessary and sufficient for triggering neurogenic inflammation. An alternative hypothesis could reconcile previous and present findings on the role of NPY and NPY receptors in neurogenic inflammation: an opposing role of Y1 and Y2 receptors (or other Y receptors) in the excitability of capsaicin-sensitive nerve terminals could exist if both receptors are tonically stimulated by endogenous NPY. In wild-type animals, the exogenous administration of NPY has an inhibitory effect on capsaicininduced inflammatory responses, possibly because of a preferential stimulation of Y2 receptors. In Y1–/– animals, endogenous NPY could be sufficient for the inhibition of the excitability of capsaicin-sensitive nerve terminals through the stimulation of Y2 receptors. This hypothesis could be tested either through the construction of Y2–/– mice, or with the use of already available selective Y2 receptor antagonists. 1 Naveilhan, P. et al. (2001) Reduced antinociception and plasma protein extravasation in mice lacking a neuropeptide Y receptor. Nature 409, 513–517
Alessandro Lecci [email protected]
221
In Brief
Heparin and cancer revisited The notion that the common anticoagulant heparin could be used to stem the spread of cancer is not new. It has long been known that the drug, administered intravenously, can inhibit tumour metastasis. But heparin therapy can be difficult to manage on an outpatient basis, and the subject fell out of favour when oral anticoagulants were found to have little or no anti-metastatic effect. Now, Lubor Borsig and co-workers hope that their findings (Proc. Natl. Acad. Sci. U. S. A. 2001, Vol. 98, pp. 3352–3357) will put heparin therapy for metastasis prevention back on the clinical agenda. The group confirmed that heparin’s antimetastatic action is not due to its ability to prevent blood clotting; instead, they found that the drug blocks metastatic progression by inhibiting P-selectin-based platelet interactions with tumour cell-surface mucins. Stripped of their ‘platelet cloak’, tumour cells were left open to attack by macrophages. A single dose of heparin, which blocked early platelet–tumour-cell interactions, was sufficient to prevent longterm organ colonization. The authors suggest that heparin treatment be explored with a new mechanistic paradigm in mind. RC
Disappointment for Parkinson’s disease patients The first controlled trials of foetal transplants of dopamine-containing neurones in patients with severe Parkinson’s disease have ended in disappointment. Curt Freed and colleagues (New Engl. J. Med. 2001, Vol. 344, pp. 710–719) showed that fibre outgrowth from neurones implanted in the putamen occurred in the majority of cases. However, the treatment, previously hailed as a potential cure for the disorder, was found to improve symptoms only in younger patients. Subjects over 60 years of age – which represent the majority of those suffering from Parkinson’s disease – did not appear to benefit. Moreover, 15% of patients developed dystonia and dyskinesias after improvement in the first year; these distressing developments were ascribed to an excess of dopamine. Levodopa and other dopaminergic drugs remain the principal treatment for Parkinson’s disease patients. RC
http://tips.trends.com 0165-6147/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.