- Email: [email protected]
NMDA receptor blockade: A novel avenue for tobacco intervention?
Correspondence removal of the thymus gland has been well established as an effective therapy in MG and become an accepted therapeutic option worldwide [1,2], mainly because it results in remission rates as high as 42% and clinical improvement in up to 94% of all cases [3]. Most chronic autoimmune diseases are mediated by CD4+ T cells, and the recruitment of autoreactive CD4+ T cells specific for T antigens might permit the development of a similar situation, with the immune response directed towards the specific destruction of the transformed tissue [4]. Thymus gland, as the site of T cell education with resulting self-tolerance, plays a central role in the pathogenesis of MG and other autoimmune diseases. Thymectomy could reduce the amount of autoreactive CD4+ T cells and provide drastic influence on the immune response mediated by them, and therefore, inhibit the specific destruction of the target tissues in the autoimmune diseases. To the patients with autoimmune diseases, immunosuppressive treatment is one of the most important methods; however, these patients will suffer from the undesirable side effect of immunosuppressive agent and represent drug resistance with the progression of disease. Therefore, seeking effective therapeutic methods with more acceptances has been paid more attention in the research field of autoimmune diseases. Thus makes us hypothesize that thymectomy might become a potential therapeutic strategy of other autoimmune diseases beside MG, such as systemic lupus erythematosus and autoimmune encephalitis. Our hypothesis might provide a novel therapeutic strategy for patients with autoimmune diseases. With the aid of animal model, (for instance, exper-
1073 imental autoimmune encephalitis), this hypothesis could be partially or fully confirmed.
References [1] Jaretzki A. Thymectomy for myasthenia gravis: analysis of the controversies regarding technique and results. Neurology 1997;48(Suppl. 5):S52–63. [2] Gronseth GS, Barohn RJ. Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;55(1): 7–15. [3] Nussbaum M, Rosenthal G, Samaha F, Grinvalsky H, Quinlan M, Schmerler M. Management of myasthenia gravis by extended dissection. Surgery 1992;112:681–8. [4] Topalian SL, Gonzales MI, Parkhurst M, Li YF, Southwood S, Sette A, Rosenberg SA, Robbins PF. Melanoma-specific CD4+ T cells recognize nonmutated HLA-DR-restricted tyrosinase epitopes. J Exp Med 1996;183:1965–71.
Wei Guo 1 Yun-Ping Zhao 1 Yao-Guang Jiang * Shi-Zhi Fan Ru-Wen Wang Zhi-Ping Li Department of Thoracic Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China Tel.: +86 23 68757022; fax: +86 23 68816736 E-mail address: [email protected] (Y.-G. Jiang). 1
The two authors contributed equally to this study.
doi:10.1016/j.mehy.2007.11.003
NMDA receptor blockade: A novel avenue for tobacco intervention? The N-methyl-D-aspartate (NMDA) receptor is a glutamate activated ion channel involved in central excitatory pathways that are critical in higher brain functioning such as learning, memory and certain behaviors [1]. Additionally, excessive NMDA receptor stimulation is involved with chronic pain, addiction [1], and neuronal cell death (also know as excitotoxicity) [2]. Nicotine use enhances glutamate (excitatory) transmission via the NMDA receptor while at the
same time desensitizing GABA (inhibitory) transmission within brain reward pathways. Nicotine acts on pre-synaptic nicotinic acetylcholine receptors (nAChR) of glutamate efferents located within the prefrontal cortex. These efferents project to the ventral tegmental area (VTA) [3]. When stimulated, there is increased glutamate release from these efferents into the VTA. Here, the increased glutamate interacts with NMDA receptors located post-synaptically on VTA dopamine neurons that
1074 project into the shell of the nucleus accumbens, increasing their firing rate [3]. Simultaneously, nicotine desensitizes GABA receptors [3], in essence inhibiting this inhibitor of dopamine release. The net result is increased dopamine release into the shell of the nucleus accumbens which is responsible for the rewarding and addictive properties of many drugs of abuse, including nicotine. From these observations, it appears that NMDA receptors may play a role in nicotine use, and that blockade of these receptors may reduce the nicotine-induced excitatory glutamate response with the VTA [3]. Hypothetically, such a blockade may have therapeutic implications for tobacco cessation. Two currently marketed drugs – memantine (Namenda) and acamprosate (Campral) – have activity against the excitatory effects of glutamate. Memantine is a low affinity NMDA receptor antagonist with weaker antagonism at nicotinic acetylcholine receptors [2]. It has been approved for use in Alzheimer’s disease, likely exerting its action by ameliorating glutamatergic excitotoxicity. There is also evidence that memantine may have a positive role in nicotine abuse [4], although a pilot study among 40 smokers [5] revealed that memantine helped only with certain aspects of nicotine’s effects and did not facilitate smoking reduction. It should be noted that, while memantine did not help with smoking reduction in that study, there were trends toward decreased craving scores that failed to reach statistical significance likely due to a small sample size [5]. Importantly, memantine is not associated with a significant frequency of adverse events. Acamprosate, approved for use in alcoholism, likely exerts its action by restoring the imbalance
Correspondence between glutamate excitatory and GABA inhibitory states [6]. It has not been studied in connection with nicotine use. Aside from occasional diarrhea with acamprosate, both drugs are generally well tolerated and thus appear safe for testing in smoking cessation.
References [1] Popescu G. Mechanism-based targeting of NMDA receptor functions. Cell Mol Life Sci 2005;62:2100–11. [2] Kemp JA, McKernan RM. NMDA recptor pathways as drug targets. Nat Neurosci 2002;5:1039–42. [3] Kenny PJ, Markou A. Neurobiology of the nicotine withdrawal syndrome. Pharm Biochem Behav 2001;70:531–49. [4] Blokhina EA, Kashkin VA, Zvartan EE, Danysz W, Bespolov Ay. Effects of nicotinic and NMDA receptor channel blockers on intravenous cocaine and nicotine self-administration. Eur Neuropsychopharm 2005;15:219–25. [5] Thuerauf N, Lunkenheimer J, Lunkenheimer B, et al. Memantine fails to facilitate partial cigarette deprivation in smokers—no role of memantine in the treatment of nicotine dependency? J Neural Transm. [Epub ahead of print]. [6] De Witte P. Imbalance between neuroexcitatory and neuroinhibitory amino acids causes craving for alcohol. Addict Behav:1325–39.
John G. Spangler Department of Family and Community Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, United States Tel.: +1 336 716 2238; fax: +1 336 716 1297 E-mail address: [email protected]
doi:10.1016/j.mehy.2007.11.001
A new treatment for chronic itch? I previously suggested with colleagues that central post-stroke pain (CPSP) may be alleviated by caloric vestibular stimulation [1]. We have subsequently found evidence to support this hypothesis [2]. I would also like to extend this proposal to suggest that vestibular stimulation may also bring relief from chronic itch. The thermosensory disinhibition model of CPSP [3] is based on the fact that physiologically temperatures of less than 25 °C actually activate both cold and pain receptors in the skin. The pain
receptors travel to the anterior cingulate cortex (ACC), and the cold receptors input (via the lateral thalamus) to the thermosensory cortex, in the dorsal posterior insula (dpIns), which acts (via the brainstem) to suppress the generation of pain at the ACC. However, cold receptor activation occurs in a bell-shaped curve and when the temperature falls below 8 °C it is largely just pain receptors that are activated in the skin and the organism is driven to protect itself from potentially harmful temperatures.
1073 imental autoimmune encephalitis), this hypothesis could be partially or fully confirmed.
References [1] Jaretzki A. Thymectomy for myasthenia gravis: analysis of the controversies regarding technique and results. Neurology 1997;48(Suppl. 5):S52–63. [2] Gronseth GS, Barohn RJ. Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;55(1): 7–15. [3] Nussbaum M, Rosenthal G, Samaha F, Grinvalsky H, Quinlan M, Schmerler M. Management of myasthenia gravis by extended dissection. Surgery 1992;112:681–8. [4] Topalian SL, Gonzales MI, Parkhurst M, Li YF, Southwood S, Sette A, Rosenberg SA, Robbins PF. Melanoma-specific CD4+ T cells recognize nonmutated HLA-DR-restricted tyrosinase epitopes. J Exp Med 1996;183:1965–71.
Wei Guo 1 Yun-Ping Zhao 1 Yao-Guang Jiang * Shi-Zhi Fan Ru-Wen Wang Zhi-Ping Li Department of Thoracic Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, PR China Tel.: +86 23 68757022; fax: +86 23 68816736 E-mail address: [email protected] (Y.-G. Jiang). 1
The two authors contributed equally to this study.
doi:10.1016/j.mehy.2007.11.003
NMDA receptor blockade: A novel avenue for tobacco intervention? The N-methyl-D-aspartate (NMDA) receptor is a glutamate activated ion channel involved in central excitatory pathways that are critical in higher brain functioning such as learning, memory and certain behaviors [1]. Additionally, excessive NMDA receptor stimulation is involved with chronic pain, addiction [1], and neuronal cell death (also know as excitotoxicity) [2]. Nicotine use enhances glutamate (excitatory) transmission via the NMDA receptor while at the
same time desensitizing GABA (inhibitory) transmission within brain reward pathways. Nicotine acts on pre-synaptic nicotinic acetylcholine receptors (nAChR) of glutamate efferents located within the prefrontal cortex. These efferents project to the ventral tegmental area (VTA) [3]. When stimulated, there is increased glutamate release from these efferents into the VTA. Here, the increased glutamate interacts with NMDA receptors located post-synaptically on VTA dopamine neurons that
1074 project into the shell of the nucleus accumbens, increasing their firing rate [3]. Simultaneously, nicotine desensitizes GABA receptors [3], in essence inhibiting this inhibitor of dopamine release. The net result is increased dopamine release into the shell of the nucleus accumbens which is responsible for the rewarding and addictive properties of many drugs of abuse, including nicotine. From these observations, it appears that NMDA receptors may play a role in nicotine use, and that blockade of these receptors may reduce the nicotine-induced excitatory glutamate response with the VTA [3]. Hypothetically, such a blockade may have therapeutic implications for tobacco cessation. Two currently marketed drugs – memantine (Namenda) and acamprosate (Campral) – have activity against the excitatory effects of glutamate. Memantine is a low affinity NMDA receptor antagonist with weaker antagonism at nicotinic acetylcholine receptors [2]. It has been approved for use in Alzheimer’s disease, likely exerting its action by ameliorating glutamatergic excitotoxicity. There is also evidence that memantine may have a positive role in nicotine abuse [4], although a pilot study among 40 smokers [5] revealed that memantine helped only with certain aspects of nicotine’s effects and did not facilitate smoking reduction. It should be noted that, while memantine did not help with smoking reduction in that study, there were trends toward decreased craving scores that failed to reach statistical significance likely due to a small sample size [5]. Importantly, memantine is not associated with a significant frequency of adverse events. Acamprosate, approved for use in alcoholism, likely exerts its action by restoring the imbalance
Correspondence between glutamate excitatory and GABA inhibitory states [6]. It has not been studied in connection with nicotine use. Aside from occasional diarrhea with acamprosate, both drugs are generally well tolerated and thus appear safe for testing in smoking cessation.
References [1] Popescu G. Mechanism-based targeting of NMDA receptor functions. Cell Mol Life Sci 2005;62:2100–11. [2] Kemp JA, McKernan RM. NMDA recptor pathways as drug targets. Nat Neurosci 2002;5:1039–42. [3] Kenny PJ, Markou A. Neurobiology of the nicotine withdrawal syndrome. Pharm Biochem Behav 2001;70:531–49. [4] Blokhina EA, Kashkin VA, Zvartan EE, Danysz W, Bespolov Ay. Effects of nicotinic and NMDA receptor channel blockers on intravenous cocaine and nicotine self-administration. Eur Neuropsychopharm 2005;15:219–25. [5] Thuerauf N, Lunkenheimer J, Lunkenheimer B, et al. Memantine fails to facilitate partial cigarette deprivation in smokers—no role of memantine in the treatment of nicotine dependency? J Neural Transm. [Epub ahead of print]. [6] De Witte P. Imbalance between neuroexcitatory and neuroinhibitory amino acids causes craving for alcohol. Addict Behav:1325–39.
John G. Spangler Department of Family and Community Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, United States Tel.: +1 336 716 2238; fax: +1 336 716 1297 E-mail address: [email protected]
doi:10.1016/j.mehy.2007.11.001
A new treatment for chronic itch? I previously suggested with colleagues that central post-stroke pain (CPSP) may be alleviated by caloric vestibular stimulation [1]. We have subsequently found evidence to support this hypothesis [2]. I would also like to extend this proposal to suggest that vestibular stimulation may also bring relief from chronic itch. The thermosensory disinhibition model of CPSP [3] is based on the fact that physiologically temperatures of less than 25 °C actually activate both cold and pain receptors in the skin. The pain
receptors travel to the anterior cingulate cortex (ACC), and the cold receptors input (via the lateral thalamus) to the thermosensory cortex, in the dorsal posterior insula (dpIns), which acts (via the brainstem) to suppress the generation of pain at the ACC. However, cold receptor activation occurs in a bell-shaped curve and when the temperature falls below 8 °C it is largely just pain receptors that are activated in the skin and the organism is driven to protect itself from potentially harmful temperatures.