Role of nicotinic acetylcholine receptor subtypes α4β2 and α7 in nicotine-ethanol interaction and cross-tolerance: functional correlation with cerebellar nitric oxide

The prevalent co-abuse of alcohol and tobacco products results in higher morbidity and mortality rates than those caused by either drug alone, thus posing a serious health problem. Understanding the interactive relationship between nicotine and ethanol might lead to effective strategies for the treatment of co-addiction. This dissertation project was designed to investigate the role of two nicotinic-acetylcholine-receptor (nAChR) subtypes (i.e. α4β2 and α7) on nicotine’s attenuation of ethanol ataxia and its functional correlation with alterations in cerebellar nitric oxide concentration. Expression levels of cerebellar α4β2 and α7 subtypes were also determined immunohistochemically. Ethanol (2g/kg;i.p.)-induced ataxia was assessed by Rotorod in stereotaxically cannulated CD-1 male mice following the acute or repeated intracerebellar (ICB) microinfusions of α4β2- and α7-selective agonists, RJR-2403 and PNU-282987. Acute RJR-2403 (31, 62, 125ng), and PNU-282987 (25ng, 250ng, 2.5μg), dose-dependently reduced ethanol ataxia. Pretreatment with potent α4β2 [Dihydro-β-erythroidine (DHβE)] and α7 [Methyllycaconitine (MLA)]-subtype–selective antagonists prevented RJR-2403 and PNU-282987’s attenuation of ethanol ataxia, respectively. Both antagonists also offset nicotine’s reduction of ethanol ataxia, confirming the contribution of α4β2 and α7 subtype in ethanol ataxia. There was no tonic role of either subtype in ethanol ataxia. Additionally, ICB α4β2 and α7 subtype antisense treatment data correspond with agonist-induced behavioral responses. Animals repeatedly microinfused with RJR- 2403 or PNU-282987 became tolerant to ethanol ataxia. The observed cross-tolerance was faster in onset and longer in duration with PNU-282987 than RJR-2403. Pretreatment with DHβE and MLA, prevented the development of cross-tolerance. The cerebellar nitrite+nitrate (NOx) levels were significantly enhanced and reduced following acute/repeated RJR- 2403/PNU-282987 microinfusion and acute ethanol injection, respectively. Pretreatment with RJR- 2403 or PNU-282987 followed by ethanol prevented the ethanol-induced decrease in NOx concentration in both acute and repeated treatment paradigms, thus correlating the decrease in NOx concentration with ataxia and elevation with attenuation of ataxia. Both α4β2 and α7 subtypes exhibited high immunoreactivity in Purkinje, however, expression in molecular and granular cell layers was sparse. Overall, the results of the project support the role of α4β2 and α7 subtypes in the functional interaction between nicotine and acute ethanol ataxia, with NO-cGMP signaling as a participating factor.Ph.D

GENDER DYSPHORIA: A MEDICAL AND ETHICAL PERPLEXITY AS DISTINCT FROM REALITY AND THE RATIONAL APPROACH FOR MUSLIM YOUNG PEOPLE

Gender dysphoria (GD)-perceived gender identity and the biological sex has been a wholly enigma and a source of contention between experts of various disciplines since long. This is a narrative review of the medical literature utilizing PubMed, Scopus, and Web of science databases, on the social status of GD patients, their therapeutic options, as well as the medical and ethical debate on GD that are of especial interest to the Muslim readers. Gender dysphoric patients or transgender people have a long history of social discrimination, marginalization, abuse, and neglect all around the world. Currently, large scale social developments supporting of transgender rights are rapidly underway in the west. Clinical evidence-based guidelines have also been published and are available for the management of GD, albeit with some medical and ethical concerns. On the other hand, the transgender community is continued to suffer profoundly in the developing and majority of Muslim nations, due to generalized unawareness, neglect, cultural and religious boundaries on this issue. Currently, Muslim youth or young adults are showing passionate interest in GD and are actively seeking information to comprehend its complexities, but they face more dilemma on this matter than the people in the West. This article addresses and discusses key transgender issues and controversies and provides a logical explanation that demonstrates that GD is real medical condition needing attention and that its treatment guidelines are justified. We hope this article will stimulate a new and broader perspective in minds of young Muslims and will urge them to take pragmatic steps in alleviating the travails of long-suffering and neglected transgender community

Neuroantigen-specific, tolerogenic vaccines: GM-CSF is a fusion partner that facilitates tolerance rather than immunity to dominant self-epitopes of myelin in murine models of experimental autoimmune encephalomyelitis (EAE)

<p>Abstract</p> <p>Background</p> <p>Vaccination strategies that elicit antigen-specific tolerance are needed as therapies for autoimmune disease. This study focused on whether cytokine-neuroantigen (NAg) fusion proteins could inhibit disease in chronic murine models of experimental autoimmune encephalomyelitis (EAE) and thus serve as potential therapeutic modalities for multiple sclerosis.</p> <p>Results</p> <p>A fusion protein comprised of murine GM-CSF as the N-terminal domain and the encephalitogenic MOG35-55 peptide as the C-terminal domain was tested as a tolerogenic, therapeutic vaccine (TTV) in the C57BL/6 model of EAE. Administration of GMCSF-MOG before active induction of EAE, or alternatively, at the onset of EAE blocked the development and progression of EAE. Covalent linkage of the GM-CSF and MOG35-55 domains was required for tolerogenic activity. Likewise, a TTV comprised of GM-CSF and PLP139-151 was a tolerogen in the SJL model of EAE.</p> <p>Conclusion</p> <p>These data indicated that fusion proteins containing GM-CSF coupled to myelin auto-antigens elicit tolerance rather than immunity.</p

The Extracellular Domain of Myelin Oligodendrocyte Glycoprotein Elicits Atypical Experimental Autoimmune Encephalomyelitis in Rat and Species

Atypical models of experimental autoimmune encephalomyelitis (EAE) are advantageous in that the heterogeneity of clinical signs appears more reflective of those in multiple sclerosis (MS). Conversely, models of classical EAE feature stereotypic progression of an ascending flaccid paralysis that is not a characteristic of MS. The study of atypical EAE however has been limited due to the relative lack of suitable models that feature reliable disease incidence and severity, excepting mice deficient in gamma-interferon signaling pathways. In this study, atypical EAE was induced in Lewis rats, and a related approach was effective for induction of an unusual neurologic syndrome in a cynomolgus macaque. Lewis rats were immunized with the rat immunoglobulin variable (IgV)-related extracellular domain of myelin oligodendrocyte glycoprotein (IgV-MOG) in complete Freund’s adjuvant (CFA) followed by one or more injections of rat IgV-MOG in incomplete Freund’s adjuvant (IFA). The resulting disease was marked by torticollis, unilateral rigid paralysis, forelimb weakness, and high titers of anti-MOG antibody against conformational epitopes of MOG, as well as other signs of atypical EAE. A similar strategy elicited a distinct atypical form of EAE in a cynomolgus macaque. By day 36 in the monkey, titers of IgG against conformational epitopes of extracellular MOG were evident, and on day 201, the macaque had an abrupt onset of an unusual form of EAE that included a pronounced arousal-dependent, transient myotonia. The disease persisted for 6–7 weeks and was marked by a gradual, consistent improvement and an eventual full recovery without recurrence. These data indicate that one or more boosters of IgV-MOG in IFA represent a key variable for induction of atypical or unusual forms of EAE in rat and Macaca species. These studies also reveal a close correlation between humoral immunity against conformational epitopes of MOG, extended confluent demyelinating plaques in spinal cord and brainstem, and atypical disease induction

De Novo Evaluation of Gender Dysphoria Misconceptions and Islamic Religious Perplexity: Is there any Chance of Reconciliation?

Gender dysphoria [GD] or a sex and gender discord that leads to enormous psychological suffering in some variants of transgender people is a highly complex and debatable subject. Muslim culture, religious and ethical values pose more challenges to the acceptance of GD than the Western system. The purpose of this narrative review is to present and discuss GD misconceptions and contrasting Islamic views with a fresh perspective and a rational approach in light of current advancements in this field. Since there are no directives in the Holy Quran and Hadith on matters of GD, Muslims have been polarized regarding GD. The so-called “liberal scholars” corroborate the scientific fact and view GD patients as a medical condition, which necessitates contemporary therapeutic interventions. Conversely, the so-called “conservative approaches” regard GD a delusional thinking probably arising from a mental illness, or a spiritual immorality, which necessitates psychotherapy or zealous religious guidance. Due to the religious tensions, generalized unawareness, and scarcity of the quality multifaceted research, there is widespread misconceptions and hostility toward transgender people in Islamic culture. The critical appraisal of the Islamic debate on GD proves that despite its ambiguity and intricacies, GD remains a stark reality and merits resolution. Though conflicted on GD, Islamic jurists concur that Islamic laws founded on core principles of love, and respect for all dictate rational reasoning, and enlightened approach on obscure matters. Young Muslims can help reconcile GD conflict in Islamic societies by initiating intra-faith dialogues and engaging their religious scholars in clinical and patient-centered research to broaden their perspective. Collaborative efforts can prompt conservative Islamic scholars to re-negotiate their antagonistic stance on GD or SRT. Islamic leaders can also influence local governments and policy makers to develop policies to improve the welfare of long-ignored transgender people that deserve attention, empathy, and treatment on moral and religious grounds

Role of nicotinic acetylcholine receptor subtypes α4β2 and α7 in nicotine-ethanol interaction and cross-tolerance: functional correlation with cerebellar nitric oxide

The prevalent co-abuse of alcohol and tobacco products results in higher morbidity and mortality rates than those caused by either drug alone thus posing a serious health problem. Understanding the interactive relationship between nicotine and ethanol might lead to effective strategies for the treatment of co-addiction. This dissertation project was designed to investigate the role of two nicotinic-acetylcholine-receptor (nAChR) subtypes (i.e. α4β2 and α7) on nicotine’s attenuation of ethanol ataxia and its functional correlation with alterations in cerebellar nitric oxide concentration. Expression levels of cerebellar α4β2 and α7 subtypes were also determined immunohistochemically. Ethanol (2g/kg;i.p.)-induced ataxia was assessed by Rotorod in stereotaxically cannulated CD-1 male mice following the acute or repeated intracerebellar (ICB) microinfusions of α4β2- and α7-selective agonists RJR-2403 and PNU-282987. Acute RJR-2403 (31 62 125ng) and PNU-282987 (25ng 250ng 2.5μg) dose-dependently reduced ethanol ataxia. Pretreatment with potent α4β2 [Dihydro-β-erythroidine (DHβE)] and α7 [Methyllycaconitine (MLA)]-subtype–selective antagonists prevented RJR-2403 and PNU-282987’s attenuation of ethanol ataxia respectively. Both antagonists also offset nicotine’s reduction of ethanol ataxia confirming the contribution of α4β2 and α7 subtype in ethanol ataxia. There was no tonic role of either subtype in ethanol ataxia. Additionally ICB α4β2 and α7 subtype antisense treatment data correspond with agonist-induced behavioral responses. Animals repeatedly microinfused with RJR- 2403 or PNU-282987 became tolerant to ethanol ataxia. The observed cross-tolerance was faster in onset and longer in duration with PNU-282987 than RJR-2403. Pretreatment with DHβE and MLA prevented the development of cross-tolerance. The cerebellar nitrite+nitrate (NOx) levels were significantly enhanced and reduced following acute/repeated RJR- 2403/PNU-282987 microinfusion and acute ethanol injection respectively. Pretreatment with RJR- 2403 or PNU-282987 followed by ethanol prevented the ethanol-induced decrease in NOx concentration in both acute and repeated treatment paradigms thus correlating the decrease in NOx concentration with ataxia and elevation with attenuation of ataxia. Both α4β2 and α7 subtypes exhibited high immunoreactivity in Purkinje however expression in molecular and granular cell layers was sparse. Overall the results of the project support the role of α4β2 and α7 subtypes in the functional interaction between nicotine and acute ethanol ataxia with NO-cGMP signaling as a participating factor

ROLE OF NICOTINIC ACETYLCHOLINE RECEPTOR SUBTYPES &#9454&#9462 AND &#9457 IN NICOTINE-ETHANOL INTERACTION AND CROSS-TOLERANCE: FUNCTIONAL CORRELATION WITH CEREBELLAR NITRIC OXIDE

The prevalent co-abuse of alcohol and tobacco products results in higher morbidity and mortality rates than those caused by either drug alone, thus posing a serious health problem. Understanding the interactive relationship between nicotine and ethanol might lead to effective strategies for the treatment of co-addiction. This dissertation project was designed to investigate the role of two nicotinic-acetylcholine-receptor (nAChR) subtypes (i.e. &amp;#945;4&amp;#946;2 and &amp;#945;7) on nicotine's attenuation of ethanol ataxia and its functional correlation with alterations in cerebellar nitric oxide concentration. Expression levels of cerebellar &amp;#945;4&amp;#946;2 and &amp;#945;7 subtypes were also determined immunohistochemically.   Ethanol (2g/kg;i.p.)-induced ataxia was assessed by Rotorod in stereotaxically cannulated CD-1 male mice following the acute or repeated intracerebellar (ICB) microinfusions of &amp;#945;4&amp;#946;2- and &amp;#945;7-selective agonists, RJR-2403 and PNU-282987. Acute RJR-2403 (31, 62, 125ng), and PNU-282987 (25ng, 250ng, 2.5µg), dose-dependently reduced ethanol ataxia. Pretreatment with potent &amp;#945;4&amp;#946;2 [Dihydro-&amp;#946;-erythroidine (DH&amp;#946;E)] and &amp;#945;7 [Methyllycaconitine (MLA)]-subtype-selective antagonists prevented RJR-2403 and PNU-282987's attenuation of ethanol ataxia, respectively. Both antagonists also offset nicotine's reduction of ethanol ataxia, confirming the contribution of &amp;#945;4&amp;#946;2 and &amp;#945;7 subtype in ethanol ataxia. There was no tonic role of either subtype in ethanol ataxia. Additionally, ICB &amp;#945;4&amp;#946;2 and &amp;#945;7 subtype antisense treatment data correspond with agonist-induced behavioral responses. Animals repeatedly microinfused with RJR- 2403 or PNU-282987 became tolerant to ethanol ataxia. The observed cross-tolerance was faster in onset and longer in duration with PNU-282987 than RJR-2403. Pretreatment with DH&amp;#946;E and MLA, prevented the development of cross-tolerance.   The cerebellar nitrite+nitrate (NOx) levels were significantly enhanced and reduced following acute/repeated RJR- 2403/PNU-282987 microinfusion and acute ethanol injection, respectively. Pretreatment with RJR- 2403 or PNU-282987 followed by ethanol prevented the ethanol-induced decrease in NOx concentration in both acute and repeated treatment paradigms, thus correlating the decrease in NOx concentration with ataxia and elevation with attenuation of ataxia. Both &amp;#945;4&amp;#946;2 and &amp;#945;7 subtypes exhibited high immunoreactivity in Purkinje, however, expression in molecular and granular cell layers was sparse. Overall, the results of the project support the role of &amp;#945;4&amp;#946;2 and &amp;#945;7 subtypes in the functional interaction between nicotine and acute ethanol ataxia, with NO-cGMP signaling as a participating factor.  &amp;#8195; 

Role of nicotinic acetylcholine receptor subtypes a4ß2 and a7 in nicotine-ethanol interaction and cross-tolerance: functional correlation with cerebellar nitric oxide

The prevalent co-abuse of alcohol and tobacco products results in higher morbidity and mortality rates than those caused by either drug alone, thus posing a serious health problem. Understanding the interactive relationship between nicotine and ethanol might lead to effective strategies for the treatment of co-addiction. This dissertation project was designed to investigate the role of two nicotinic-acetylcholine-receptor (nAChR) subtypes (i.e. a4ß2 and a7) on nicotine’s attenuation of ethanol ataxia and its functional correlation with alterations in cerebellar nitric oxide concentration. Expression levels of cerebellar a4ß2 and a7 subtypes were also determined immunohistochemically.\r\n\r\n\r\n\r\nEthanol (2g/kg\;i.p.)-induced ataxia was assessed by Rotorod in stereotaxically cannulated CD-1 male mice following the acute or repeated intracerebellar (ICB) microinfusions of a4ß2- and a7-selective agonists, RJR-2403 and PNU-282987. Acute RJR-2403 (31, 62, 125ng), and PNU-282987 (25ng, 250ng, 2.5µg), dose-dependently reduced ethanol ataxia. Pretreatment with potent a4ß2 [Dihydro-ß-erythroidine (DHßE)] and a7 [Methyllycaconitine (MLA)]-subtype–selective antagonists prevented RJR-2403 and PNU-282987’s attenuation of ethanol ataxia, respectively. Both antagonists also offset nicotine’s reduction of ethanol ataxia, confirming the contribution of a4ß2 and a7 subtype in ethanol ataxia. There was no tonic role of either subtype in ethanol ataxia. Additionally, ICB a4ß2 and a7 subtype antisense treatment data correspond with agonist-induced behavioral responses. Animals repeatedly microinfused with RJR- 2403 or PNU-282987 became tolerant to ethanol ataxia. The observed cross-tolerance was faster in onset and longer in duration with PNU-282987 than RJR-2403. Pretreatment with DHßE and MLA, prevented the development of cross-tolerance.\r\n\r\n\r\n\r\nThe cerebellar nitrite+nitrate (NOx) levels were significantly enhanced and reduced following acute/repeated RJR- 2403/PNU-282987 microinfusion and acute ethanol\r\n\r\n\r\n\r\ninjection, respectively. Pretreatment with RJR- 2403 or PNU-282987 followed by ethanol prevented the ethanol-induced decrease in NOx concentration in both acute and repeated treatment paradigms, thus correlating the decrease in NOx concentration with ataxia and elevation with attenuation of ataxia. Both a4ß2 and a7 subtypes exhibited high immunoreactivity in Purkinje, however, expression in molecular and granular cell layers was sparse. Overall, the results of the project support the role of a4ß2 and a7 subtypes in the functional interaction between nicotine and acute ethanol ataxia, with NO-cGMP signaling as a participating factor

The extracellular domain of myelin oligodendrocyte glycoprotein elicits atypical experimental autoimmune encephalomyelitis in rat and Macaque species

Atypical models of experimental autoimmune encephalomyelitis (EAE) are advantageous in that the heterogeneity of clinical signs appears more reflective of those in multiple sclerosis (MS). Conversely, models of classical EAE feature stereotypic progression of an ascending flaccid paralysis that is not a characteristic of MS. The study of atypical EAE however has been limited due to the relative lack of suitable models that feature reliable disease incidence and severity, excepting mice deficient in gamma-interferon signaling pathways. In this study, atypical EAE was induced in Lewis rats, and a related approach was effective for induction of an unusual neurologic syndrome in a cynomolgus macaque. Lewis rats were immunized with the rat immunoglobulin variable (IgV)-related extracellular domain of myelin oligodendrocyte glycoprotein (IgV-MOG) in complete Freund"s adjuvant (CFA) followed by one or more injections of rat IgV-MOG in incomplete Freund"s adjuvant (IFA). The resulting disease was marked by torticollis, unilateral rigid paralysis, forelimb weakness, and high titers of anti-MOG antibody against conformational epitopes of MOG, as well as other signs of atypical EAE. A similar strategy elicited a distinct atypical form of EAE in a cynomolgus macaque. By day 36 in the monkey, titers of IgG against conformational epitopes of extracellular MOG were evident, and on day 201, the macaque had an abrupt onset of an unusual form of EAE that included a pronounced arousal-dependent, transient myotonia. The disease persisted for 6--7 weeks and was marked by a gradual, consistent improvement and an eventual full recovery without recurrence. These data indicate that one or more boosters of IgV-MOG in IFA represent a key variable for induction of atypical or unusual forms of EAE in rat and Macaca species. These studies also reveal a close correlation between humoral immunity against conformational epitopes of MOG, extended confluent demyelinating plaques in spinal cord and brainstem, and atypical disease induction