Medicine and Health Sciences Commons^™

Mechanisms Of Primary Axonal Damage In A Viral Model Of Multiple Sclerosis., Jayasri Das Sarma, Lawrence C. Kenyon, Susan T. Hingley, Kenneth S. Shindler

Department of Neurology Faculty Papers

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Recent studies have demonstrated that significant axonal injury also occurs in MS patients and correlates with neurological dysfunction, but it is not known whether this neuronal damage is a primary disease process, or occurs only secondary to demyelination. In the current studies, neurotropic strains of mouse hepatitis virus (MHV) that induce meningitis, encephalitis, and demyelination in the CNS, an animal model of MS, were used to evaluate mechanisms of axonal injury. The pathogenic properties of genetically engineered isogenic spike protein recombinant demyelinating and nondemyelinating strains of MHV were compared. …

Cardioprotective Effect Of Adiponectin Is Partially Mediated By Its Ampk-Independent Antinitrative Action., Yajing Wang, Ling Tao, Yuexing Yuan, Wayne Bond Lau, Rong Li, Bernard L. Lopez, Theodore A. Christopher, Rong Tian, Xin-Liang Ma

Department of Emergency Medicine Faculty Papers

Adiponectin (APN) exerts its metabolic regulation largely through AMP-dependent protein kinase (AMPK). However, the role of AMPK in APN's antiapoptotic effect in ischemic-reperfused (I/R) adult cardiomyocytes remains incompletely understood. The present study was designed to determine the involvement of AMPK in the antiapoptotic signaling of APN. Cardiomyocytes from adult male mice overexpressing a dominant-negative alpha(2)-subunit of AMPK (AMPK-DN) or wild-type (WT) littermates were subjected to simulated I/R (SI/R) and pretreated with 2 microg/ml globular domain of APN (gAPN) or vehicle. SI/R-induced cardiomyocyte apoptosis was modestly increased in AMPK-DN cardiomyocytes (P < 0.05). Treatment with gAPN significantly reduced SI/R-induced apoptosis in WT cardiomyocytes as well as in AMPK-DN cardiomyocytes, indicating that the antiapoptotic effect of gAPN is partially AMPK independent. Furthermore, gAPN-induced endothelial nitric oxide synthase (eNOS) phosphorylation was significantly reduced in AMPK-DN cardiomyocytes, suggesting that the APN-eNOS signaling axis is impaired in AMPK-DN cardiomyocytes. Additional experiments demonstrated that treatment of AMPK-DN cardiomyocytes with gAPN reduced SI/R-induced NADPH oxidase overexpression, decreased superoxide generation, and blocked peroxynitrite formation to the same extent as that observed in WT cardiomyocytes. Collectively, our present study demonstrated that although the metabolic and eNOS activation effect of APN is largely mediated by AMPK, the superoxide-suppressing effect of APN is not mediated by AMPK, and this AMPK-independent antioxidant property of APN increased nitric oxide bioavailability and exerted significant antiapoptotic effect.

Functional Interleukin-17 Receptor A Is Expressed In Central Nervous System Glia And Upregulated In Experimental Autoimmune Encephalomyelitis., Jayasri Das Sarma, Bogoljub Ciric, Ryan Marek, Sanjoy Sadhukhan, Michael L. Caruso, Jasmine Shafagh, Denise C. Fitzgerald, Kenneth S. Shindler, Am Rostami

Department of Neurology Faculty Papers

BACKGROUND: Interleukin-17A (IL-17A) is the founding member of a novel family of inflammatory cytokines that plays a critical role in the pathogenesis of many autoimmune diseases, including multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). IL-17A signals through its receptor, IL-17RA, which is expressed in many peripheral tissues; however, expression of IL-17RA in the central nervous system (CNS) and its role in CNS inflammation are not well understood.

METHODS: EAE was induced in C57Bl/6 mice by immunization with myelin oligodendroglial glycoprotein. IL-17RA expression in the CNS was compared between control and EAE mice using RT-PCR, in situ …

Increased Susceptibility Of Spinal Muscular Atrophy Fibroblasts To Camptothecin Is P53-Independent., Chia-Yen Wu, Ilsa Gómez-Curet, Vicky L Funanage, Mena Scavina, Wenlan Wang

Department of Pediatrics Faculty Papers

BACKGROUND: Deletion or mutation(s) of the survival motor neuron 1 (SMN1) gene causes spinal muscular atrophy (SMA). The SMN protein is known to play a role in RNA metabolism, neurite outgrowth, and cell survival. Yet, it remains unclear how SMN deficiency causes selective motor neuron death and muscle atrophy seen in SMA. Previously, we have shown that skin fibroblasts from SMA patients are more sensitive to the DNA topoisomerase I inhibitor camptothecin, supporting a role for SMN in cell survival. Here, we examine the potential mechanism of camptothecin sensitivity in SMA fibroblasts.

RESULTS: Camptothecin treatment reduced the DNA relaxation activity …