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Minocycline may attenuate postherpetic neuralgia
Medical Hypotheses 73 (2009) 744–745
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Minocycline may attenuate postherpetic neuralgia Qiang Zhang *,1, Liping Peng 1, Deren Zhang *,1 Department of Pain Management, Shenzhen Nanshan Hospital, Shenzhen 518052, Guangdong Province, China
a r t i c l e
i n f o
Article history: Received 10 April 2009 Accepted 18 April 2009
s u m m a r y Postherpetic neuralgia (PHN) is a chronic pain syndrome and one of the most common complications of herpes zoster. Although the pathophysiological mechanisms involved in PHN are still largely unknown, it seems reasonable to assume that there are lesions of the peripheral afferent pain pathways and inflammation-induced damage to afferent ganglia in the spinal cord. Growing body of evidence indicates that the glial cells, particularly microglia (CNS macrophages) and astrocytes are activated following peripheral and central noxious insult and their activation is thought to play an important role in central sensitization. Glial modulators showed antiallodynic and antihyperalgesic properties in various models of experimental pain. Minocycline is a semisynthetic second generation tetracycline that exerts neuroprotection effect. It has been shown to be effective in preventing sciatic inflammatory neuropathy and intrathecal HIV-1gp120 associated pain behaviors. This agent has been used recently as a selective microglial inhibitor since it prevents microglial activation and disease progression in experimental allergic encephalomyelitis, an animal model of multiple sclerosis and other neurodegenerative diseases, such as amyotropic lateral sclerosis and Parkinson’s disease. Therefore, we hypothesize that minocycline might attenuate postherpetic neuralgia by specifically inhibiting the activation and metabolism of glial cells. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Recovery after an acute attack of herpes zoster is followed by postherpetic neuralgia (PHN) in 9–14% of all patients. Depending on the patient’s age, the severity of the acute attack of herpes zoster and the dermatome involved, the incidence of PHN may be as high as 65% [1].This chronic painful condition is characterized by severe burning and lancinating pain. This type of neuralgia is typically accompanied by allodynia (pain from non-noxious stimuli), which can persist for years [2,3]. Although the pathophysiological mechanisms involved in PHN are still largely unknown, it seems reasonable to assume that there are lesions of the peripheral afferent pain pathways and inflammation-induced damage to afferent ganglia in the spinal cord. Studies with magnetic resonance imaging demonstrate structural changes in the central nervous system in patients with PHN, but not in patients who recovered without neuralgia [4]. Varicella-zoster virus (VZV) infection is associated with induction of inflammatory cytokines, including interleukin1alpha (IL-1a) production by VZV-infected epidermal cells [5]. Human mononuclear cells have been shown to produce tumor necrosis factor-alpha (TNF-a) in vitro in response to VZV-infected fibroblasts [6]. Recent findings from human studies suggest that interleukin-8 is associated with the pain induced by inflammatory * Corresponding authors. Tel.: +86 755 86056648; fax: +86 755 26565025. E-mail address: [email protected] (Q. Zhang). 1 These authors contributed equally to this work. 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.04.028
reactions, and there are high concentrations of interleukin-8 in the cerebrospinal fluid of patients who have intractable PHN [7,8]. Furthermore, postmortem studies of patients who had prolonged PHN revealed marked inflammation around the spinal cord, with massive infiltration and accumulation of lymphocytes [9]. Recently, investigators have placed emphasis on the role of immune cells, such as invading macrophages and non-neuronal cells of the spinal cord, in nociceptive processing and the exaggerated pain states. Growing body of evidence indicates that the glial cells, particularly microglia (CNS macrophages) and astrocytes are activated following peripheral and central noxious insult and their activation is thought to play an important role in central sensitization [10–12]. Activated microglia secrete numerous substances, including growth factors, cytokines, complement factors, lipid mediators, extracellular matrix components, enzymes, free radicals, neurotoxins, nitric oxide, and prostaglandins [13], some of which are common mediators of allodynia and hyperalgesia, the characteristic features of neuropathic pain [14–17]. Further, both the glia and neurons express receptors for various neurotransmitters and neuromodulators involved in central sensitization [18,19]. The recognition of glia as powerful modulator of nociception stimulated the search for agents that specifically inhibit the activation and metabolism of glial cells leading to the discovery of glial modulators which showed antiallodynic and antihyperalgesic properties in various models of experimental pain [20,21]. The broad-spectrum antibiotic, minocycline, is a lipophilic derivative of tetracycline that has demonstrated ability to provide
Q. Zhang et al. / Medical Hypotheses 73 (2009) 744–745
neuroprotection via intraperitoneal or i.v. routes of administration [22–24]. Mechanisms attributed to the protective actions elicited by minocycline include ability to overcome glutamate-mediated excitotoxicity [25,26], antiinflammatory effects through selectively blocking the activation of microglial cells [27,28], inhibiting both cytochrome c release and caspase-dependent apoptotic neuronal death [29], as well as a capacity to antagonize the activities of matrix metalloproteinases-2 and -9 [30,31]. Additionally, It has been shown to be effective in preventing sciatic inflammatory neuropathy and intrathecal HIV-1gp120 associated pain behaviors when administered as early as one day after the injury but not on existing behavioral hypersensitivity [32].This agent has been used recently as a selective microglial inhibitor since it prevents microglial activation and disease progression in experimental allergic encephalomyelitis, an animal model of multiple sclerosis and other neurodegenerative diseases, such as amyotropic lateral sclerosis and Parkinson’s disease [29–35]. Hypothesis The treatment of PHN includes multiple agents with divergent mechanisms of action [36]. These include tricyclic antidepressants (e g., amitriptyline and nortriptyline), anticonvulsants (e.g., gabapentin), opioids, topical analgesics (e.g., lidocaine), topical capsaicin (cream), and ketamine (N-methyl-D-aspartate antagonists). Transcutaneous electrical nerve stimulation and paravertebral nerve blocks may also be effective. Even though an array of therapeutic options exists, PHN remains difficult to treat. Patients may suffer debilitating symptoms, including inadequate pain relief, despite undergoing different treatment options. Searching for new treatment alternatives is, therefore, important. As mentioned above, Minocycline is a selective microglial inhibitor. Activated microglia secretes numerous substances which are common mediators of allodynia and hyperalgesia. On the basis of the previous scientific observations, we hypothesize that minocycline might attenuate postherpetic neuralgia by specifically inhibit the activation and metabolism of glial cells As there is no data on minocycline therapy for PHN, in evaluation of our hypothesis we suggest that clinical studies must be performed to evaluate the efficacy of minocycline. References [1] Wood MJ. Herpes zoster and pain. Scand J Infect 1991(Suppl 78):53–61. [2] Rowbotham MC. Postherpetic neuralgia. Semin Neurol 1994;14:247–54. [3] Dworkin RH, Portenoy RK. Pain and its persistence in herpes zoster. Pain 1996;67:241–51. [4] Haanpaa M, Dastidar P, Weinberg A, et al. CSF and MRI findings in patients with acute herpes zoster. Neurology 1998;51:1405–11. [5] Ku CC, Zerboni L, Ito H, Graham BS, Wallace M, Arvin AM. Varicella-zoster virus transfer to skin by T cells and modulation of viral replication by epidermal cell interferon-alpha. J Exp Med 2004;200:917–25. [6] Torigo S, Ihara T, Kamiya H. IL-12, IFN-gamma, and TNF alpha released from mononuclear cells inhibit the spread of varicella-zoster virus at an early stage of varicella. Microbiol Immunol 2000;44:1027–31. [7] Kikuchi A, Kotani N, Sato T, Takamura K, Sakai I, Matsuki A. Comparative therapeutic evaluation of intrathecal versus epidural methylprednisolone for long-term analgesia in patients with intractable postherpetic neuralgia. Reg Anesth Pain Med 1999;24:287–93. [8] Kotani N, Kushikata T, Hashimoto H, et al. Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med 2000;343:1514–9. [9] Watson CPN, Deck JH, Morshead C, Van der Kooy D, Evans RJ. Postherpetic neuralgia: further post-mortem studies of cases with and without pain. Pain 1991;44:105–17. [10] Owolabi SA, Saab CY. Fractalkine and minocycline alter neuronal activity in the spinal cord dorsal horn. FEBS Lett 2006;580:4306–10.
745
[11] Zhuang Z-Y, Gerner P, Woolf CJ, Ji R-R. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to the mechanical allodynia in this neuropathic pain model. Pain 2005;114:149–59. [12] Zhuang Z-Y, Wen Y-R, Zhang DR, Borsello T, et al. A peptide c-jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci 2006;26:3551–60. [13] Minghetti L, Levi G. Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide. Prog Neurobiol 1998;54:99–125. [14] Eriksson NP, Persson JK, Svensson M, Arvidsson J, Molander C, Aldskogius H. A quantitative analysis of the microglial cell reaction in central primary sensory projection territories following peripheral nerve injury in the adult rat. Exp Brain Res 1993;96:19–27. [15] Raghavendra V, Tanga FY, DeLeo JA. Attenuation of morphine tolerance, withdrawal-induced hyperalgesia, and associated spinal inflammatory immune responses by propentofylline in rats. Neuropsychopharmacology 2004;29:327–34. [16] Wagner R, DeLeo JA, Heckman HM, Myers RR. Peripheral nerve pathology following sciatic cryoneurolysis: relationship to neuropathic behaviors in the rat. Exp Neurol 1995;133:256–64. [17] Watkins LR, Maier SF. Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2003;2:973–85. [18] Clark AK, Yip PK, Grist J, et al. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc Natl Acad Sci 2007;104:10655–60. [19] Watkins LR, Milligan ED, Maier SF. Glial activation: a driving force for pathological pain. Trends Neurosci 2001;24:450–5. [20] Ledeboer A, Liu T, Shumilla JA, et al. The glial modulatory drug AV411 attenuates mechanical allodynia in rat models of neuropathic pain. Neuron Glia Biol 2007;1:1–13. [21] Mika J, Osikowicz M, Mkuch W, Przewlocka B. Minocycline and pentoxifylline attenuate allodynia and hyperalgesia and potentiate the effects of morphine in rat and mouse models of neuropathic pain. Eur J Pharmacol 2007;560:142–9. [22] Wells JE, Hurlbert RJ, Fehlings MG, Yong VW. Neuroprotection by minocycline facilitates significant recovery from spinal cord injury in mice. Brain 2003;126:1628–37. [23] Teng YD, Choi H, Onario RC, et al. Minocycline inhibits contusiontriggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury. Proc Natl Acad Sci USA 2004;101:3071–6. [24] Xu L, Fagan SC, Waller JL, et al. Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion–reperfusion in rats. BMC Neurol 2004;4:7. [25] Tikka TM, Koistinaho JE. Minocycline provides neuroprotection against Nmethyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol 2001;166:7527–33. [26] Baptiste DC, Hartwick AT, Jollimore CA, Baldridge WH, Seigel GM, Kelly ME. An investigation of the neuroprotective effects of tetracycline derivatives in experimental models of retinal cell death. Mol Pharmacol 2004;66:1113–22. [27] Baptiste DC, Powell KJ, Jollimore CA, et al. Effects of minocycline and tetracycline on retinal ganglion cell survival after axotomy. Neuroscience 2005;134:575–82. [28] Dommergues MA, Plaisant F, Verney C, Gressens P. Early microglial activation following neonatal excitotoxic brain damage in mice: a potential target for neuroprotection. Neuroscience 2003;121:619–28. [29] Zhu S, Stavrovskaya IG, Drozda M, et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 2002;417:74–8. [30] Cho KO, La HO, Cho YJ, Sung KW, Kim SY. Minocycline attenuates white matter damage in a rat model of chronic cerebral hypoperfusion. J Neurosci Res 2006;83:285–91. [31] Brundula V, Rewcastle NB, Metz LM, Bernard CC, Yong VW. Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 2002;125:1297–308. [32] Ledeboer A, Sloane EM, Milligan ED, et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 2005;115:71–83. [33] Popovic N, Schubart A, Goetz BD, Zhang SC, Linington C, Duncan ID. Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann Neurol 2002;51:215–23. [34] Smith GA, Tsui HW, Newell EW, et al. Functional up-regulation of HERG K+channels in neoplastic hematopoietic cells. J Biol Chem 2002;277: 18528–34. [35] Wang AL, Yu AC, Lau LT, et al. Minocycline inhibits LPS-induced retinal microglia activation. Neurochem Int 2005;47:152–8. [36] Plaghki L, Adriaensen H, Morlion B, Lossignol D, Devulder J. Systematic overview of the pharmacological management of postherpetic neuralgia: an evaluation of the clinical value of critically selected drug treatments based on efficacy and safety outcomes from randomized controlled studies. Dermatology 2004;208:206–16.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Minocycline may attenuate postherpetic neuralgia Qiang Zhang *,1, Liping Peng 1, Deren Zhang *,1 Department of Pain Management, Shenzhen Nanshan Hospital, Shenzhen 518052, Guangdong Province, China
a r t i c l e
i n f o
Article history: Received 10 April 2009 Accepted 18 April 2009
s u m m a r y Postherpetic neuralgia (PHN) is a chronic pain syndrome and one of the most common complications of herpes zoster. Although the pathophysiological mechanisms involved in PHN are still largely unknown, it seems reasonable to assume that there are lesions of the peripheral afferent pain pathways and inflammation-induced damage to afferent ganglia in the spinal cord. Growing body of evidence indicates that the glial cells, particularly microglia (CNS macrophages) and astrocytes are activated following peripheral and central noxious insult and their activation is thought to play an important role in central sensitization. Glial modulators showed antiallodynic and antihyperalgesic properties in various models of experimental pain. Minocycline is a semisynthetic second generation tetracycline that exerts neuroprotection effect. It has been shown to be effective in preventing sciatic inflammatory neuropathy and intrathecal HIV-1gp120 associated pain behaviors. This agent has been used recently as a selective microglial inhibitor since it prevents microglial activation and disease progression in experimental allergic encephalomyelitis, an animal model of multiple sclerosis and other neurodegenerative diseases, such as amyotropic lateral sclerosis and Parkinson’s disease. Therefore, we hypothesize that minocycline might attenuate postherpetic neuralgia by specifically inhibiting the activation and metabolism of glial cells. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Recovery after an acute attack of herpes zoster is followed by postherpetic neuralgia (PHN) in 9–14% of all patients. Depending on the patient’s age, the severity of the acute attack of herpes zoster and the dermatome involved, the incidence of PHN may be as high as 65% [1].This chronic painful condition is characterized by severe burning and lancinating pain. This type of neuralgia is typically accompanied by allodynia (pain from non-noxious stimuli), which can persist for years [2,3]. Although the pathophysiological mechanisms involved in PHN are still largely unknown, it seems reasonable to assume that there are lesions of the peripheral afferent pain pathways and inflammation-induced damage to afferent ganglia in the spinal cord. Studies with magnetic resonance imaging demonstrate structural changes in the central nervous system in patients with PHN, but not in patients who recovered without neuralgia [4]. Varicella-zoster virus (VZV) infection is associated with induction of inflammatory cytokines, including interleukin1alpha (IL-1a) production by VZV-infected epidermal cells [5]. Human mononuclear cells have been shown to produce tumor necrosis factor-alpha (TNF-a) in vitro in response to VZV-infected fibroblasts [6]. Recent findings from human studies suggest that interleukin-8 is associated with the pain induced by inflammatory * Corresponding authors. Tel.: +86 755 86056648; fax: +86 755 26565025. E-mail address: [email protected] (Q. Zhang). 1 These authors contributed equally to this work. 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2009.04.028
reactions, and there are high concentrations of interleukin-8 in the cerebrospinal fluid of patients who have intractable PHN [7,8]. Furthermore, postmortem studies of patients who had prolonged PHN revealed marked inflammation around the spinal cord, with massive infiltration and accumulation of lymphocytes [9]. Recently, investigators have placed emphasis on the role of immune cells, such as invading macrophages and non-neuronal cells of the spinal cord, in nociceptive processing and the exaggerated pain states. Growing body of evidence indicates that the glial cells, particularly microglia (CNS macrophages) and astrocytes are activated following peripheral and central noxious insult and their activation is thought to play an important role in central sensitization [10–12]. Activated microglia secrete numerous substances, including growth factors, cytokines, complement factors, lipid mediators, extracellular matrix components, enzymes, free radicals, neurotoxins, nitric oxide, and prostaglandins [13], some of which are common mediators of allodynia and hyperalgesia, the characteristic features of neuropathic pain [14–17]. Further, both the glia and neurons express receptors for various neurotransmitters and neuromodulators involved in central sensitization [18,19]. The recognition of glia as powerful modulator of nociception stimulated the search for agents that specifically inhibit the activation and metabolism of glial cells leading to the discovery of glial modulators which showed antiallodynic and antihyperalgesic properties in various models of experimental pain [20,21]. The broad-spectrum antibiotic, minocycline, is a lipophilic derivative of tetracycline that has demonstrated ability to provide
Q. Zhang et al. / Medical Hypotheses 73 (2009) 744–745
neuroprotection via intraperitoneal or i.v. routes of administration [22–24]. Mechanisms attributed to the protective actions elicited by minocycline include ability to overcome glutamate-mediated excitotoxicity [25,26], antiinflammatory effects through selectively blocking the activation of microglial cells [27,28], inhibiting both cytochrome c release and caspase-dependent apoptotic neuronal death [29], as well as a capacity to antagonize the activities of matrix metalloproteinases-2 and -9 [30,31]. Additionally, It has been shown to be effective in preventing sciatic inflammatory neuropathy and intrathecal HIV-1gp120 associated pain behaviors when administered as early as one day after the injury but not on existing behavioral hypersensitivity [32].This agent has been used recently as a selective microglial inhibitor since it prevents microglial activation and disease progression in experimental allergic encephalomyelitis, an animal model of multiple sclerosis and other neurodegenerative diseases, such as amyotropic lateral sclerosis and Parkinson’s disease [29–35]. Hypothesis The treatment of PHN includes multiple agents with divergent mechanisms of action [36]. These include tricyclic antidepressants (e g., amitriptyline and nortriptyline), anticonvulsants (e.g., gabapentin), opioids, topical analgesics (e.g., lidocaine), topical capsaicin (cream), and ketamine (N-methyl-D-aspartate antagonists). Transcutaneous electrical nerve stimulation and paravertebral nerve blocks may also be effective. Even though an array of therapeutic options exists, PHN remains difficult to treat. Patients may suffer debilitating symptoms, including inadequate pain relief, despite undergoing different treatment options. Searching for new treatment alternatives is, therefore, important. As mentioned above, Minocycline is a selective microglial inhibitor. Activated microglia secretes numerous substances which are common mediators of allodynia and hyperalgesia. On the basis of the previous scientific observations, we hypothesize that minocycline might attenuate postherpetic neuralgia by specifically inhibit the activation and metabolism of glial cells As there is no data on minocycline therapy for PHN, in evaluation of our hypothesis we suggest that clinical studies must be performed to evaluate the efficacy of minocycline. References [1] Wood MJ. Herpes zoster and pain. Scand J Infect 1991(Suppl 78):53–61. [2] Rowbotham MC. Postherpetic neuralgia. Semin Neurol 1994;14:247–54. [3] Dworkin RH, Portenoy RK. Pain and its persistence in herpes zoster. Pain 1996;67:241–51. [4] Haanpaa M, Dastidar P, Weinberg A, et al. CSF and MRI findings in patients with acute herpes zoster. Neurology 1998;51:1405–11. [5] Ku CC, Zerboni L, Ito H, Graham BS, Wallace M, Arvin AM. Varicella-zoster virus transfer to skin by T cells and modulation of viral replication by epidermal cell interferon-alpha. J Exp Med 2004;200:917–25. [6] Torigo S, Ihara T, Kamiya H. IL-12, IFN-gamma, and TNF alpha released from mononuclear cells inhibit the spread of varicella-zoster virus at an early stage of varicella. Microbiol Immunol 2000;44:1027–31. [7] Kikuchi A, Kotani N, Sato T, Takamura K, Sakai I, Matsuki A. Comparative therapeutic evaluation of intrathecal versus epidural methylprednisolone for long-term analgesia in patients with intractable postherpetic neuralgia. Reg Anesth Pain Med 1999;24:287–93. [8] Kotani N, Kushikata T, Hashimoto H, et al. Intrathecal methylprednisolone for intractable postherpetic neuralgia. N Engl J Med 2000;343:1514–9. [9] Watson CPN, Deck JH, Morshead C, Van der Kooy D, Evans RJ. Postherpetic neuralgia: further post-mortem studies of cases with and without pain. Pain 1991;44:105–17. [10] Owolabi SA, Saab CY. Fractalkine and minocycline alter neuronal activity in the spinal cord dorsal horn. FEBS Lett 2006;580:4306–10.
745
[11] Zhuang Z-Y, Gerner P, Woolf CJ, Ji R-R. ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to the mechanical allodynia in this neuropathic pain model. Pain 2005;114:149–59. [12] Zhuang Z-Y, Wen Y-R, Zhang DR, Borsello T, et al. A peptide c-jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci 2006;26:3551–60. [13] Minghetti L, Levi G. Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide. Prog Neurobiol 1998;54:99–125. [14] Eriksson NP, Persson JK, Svensson M, Arvidsson J, Molander C, Aldskogius H. A quantitative analysis of the microglial cell reaction in central primary sensory projection territories following peripheral nerve injury in the adult rat. Exp Brain Res 1993;96:19–27. [15] Raghavendra V, Tanga FY, DeLeo JA. Attenuation of morphine tolerance, withdrawal-induced hyperalgesia, and associated spinal inflammatory immune responses by propentofylline in rats. Neuropsychopharmacology 2004;29:327–34. [16] Wagner R, DeLeo JA, Heckman HM, Myers RR. Peripheral nerve pathology following sciatic cryoneurolysis: relationship to neuropathic behaviors in the rat. Exp Neurol 1995;133:256–64. [17] Watkins LR, Maier SF. Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2003;2:973–85. [18] Clark AK, Yip PK, Grist J, et al. Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc Natl Acad Sci 2007;104:10655–60. [19] Watkins LR, Milligan ED, Maier SF. Glial activation: a driving force for pathological pain. Trends Neurosci 2001;24:450–5. [20] Ledeboer A, Liu T, Shumilla JA, et al. The glial modulatory drug AV411 attenuates mechanical allodynia in rat models of neuropathic pain. Neuron Glia Biol 2007;1:1–13. [21] Mika J, Osikowicz M, Mkuch W, Przewlocka B. Minocycline and pentoxifylline attenuate allodynia and hyperalgesia and potentiate the effects of morphine in rat and mouse models of neuropathic pain. Eur J Pharmacol 2007;560:142–9. [22] Wells JE, Hurlbert RJ, Fehlings MG, Yong VW. Neuroprotection by minocycline facilitates significant recovery from spinal cord injury in mice. Brain 2003;126:1628–37. [23] Teng YD, Choi H, Onario RC, et al. Minocycline inhibits contusiontriggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury. Proc Natl Acad Sci USA 2004;101:3071–6. [24] Xu L, Fagan SC, Waller JL, et al. Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion–reperfusion in rats. BMC Neurol 2004;4:7. [25] Tikka TM, Koistinaho JE. Minocycline provides neuroprotection against Nmethyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol 2001;166:7527–33. [26] Baptiste DC, Hartwick AT, Jollimore CA, Baldridge WH, Seigel GM, Kelly ME. An investigation of the neuroprotective effects of tetracycline derivatives in experimental models of retinal cell death. Mol Pharmacol 2004;66:1113–22. [27] Baptiste DC, Powell KJ, Jollimore CA, et al. Effects of minocycline and tetracycline on retinal ganglion cell survival after axotomy. Neuroscience 2005;134:575–82. [28] Dommergues MA, Plaisant F, Verney C, Gressens P. Early microglial activation following neonatal excitotoxic brain damage in mice: a potential target for neuroprotection. Neuroscience 2003;121:619–28. [29] Zhu S, Stavrovskaya IG, Drozda M, et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 2002;417:74–8. [30] Cho KO, La HO, Cho YJ, Sung KW, Kim SY. Minocycline attenuates white matter damage in a rat model of chronic cerebral hypoperfusion. J Neurosci Res 2006;83:285–91. [31] Brundula V, Rewcastle NB, Metz LM, Bernard CC, Yong VW. Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. Brain 2002;125:1297–308. [32] Ledeboer A, Sloane EM, Milligan ED, et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 2005;115:71–83. [33] Popovic N, Schubart A, Goetz BD, Zhang SC, Linington C, Duncan ID. Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann Neurol 2002;51:215–23. [34] Smith GA, Tsui HW, Newell EW, et al. Functional up-regulation of HERG K+channels in neoplastic hematopoietic cells. J Biol Chem 2002;277: 18528–34. [35] Wang AL, Yu AC, Lau LT, et al. Minocycline inhibits LPS-induced retinal microglia activation. Neurochem Int 2005;47:152–8. [36] Plaghki L, Adriaensen H, Morlion B, Lossignol D, Devulder J. Systematic overview of the pharmacological management of postherpetic neuralgia: an evaluation of the clinical value of critically selected drug treatments based on efficacy and safety outcomes from randomized controlled studies. Dermatology 2004;208:206–16.