TNFMedicine

TNF-alpha signaling pathways to iNOS expression in a mouse model of Alzheimer's disease: relevance for the behavioral and synaptic deficits induced by amyloid beta protein.

Title Connecting TNF-alpha signaling pathways to iNOS expression in a mouse model of Alzheimer's disease: relevance for the behavioral and synaptic deficits induced by amyloid beta protein.
Author(s) Medeiros R, Prediger RD, Passos GF, Pandolfo P, Duarte FS, Franco JL, Dafre AL, Di Giunta G, Figueiredo CP, Takahashi RN, Campos MM, Calixto JB
Institution Departamento de Farmacologia, Centro de Ciências Biológicas, Hospital Universitário-Universidade Federal de Santa Catarina, 88049-900, Florianópolis, Santa Catarina, Brazil.
Source J Neurosci 2007 May 16; 27(20) :5394-404.
Abstract Increased brain deposition of amyloid beta protein (Abeta) and cognitive deficits are classical signals of Alzheimer's disease (AD) that have been highly associated with inflammatory alterations. The present work was designed to determine the correlation between tumor necrosis factor-alpha (TNF-alpha)-related signaling pathways and inducible nitric oxide synthase (iNOS) expression in a mouse model of AD, by means of both in vivo and in vitro approaches. The intracerebroventricular injection of Abeta(1-40) in mice resulted in marked deficits of learning and memory, according to assessment in the water maze paradigm. This cognition impairment seems to be related to synapse dysfunction and glial cell activation. The pharmacological blockage of either TNF-alpha or iNOS reduced the cognitive deficit evoked by Abeta(1-40) in mice. Similar results were obtained in TNF-alpha receptor 1 and iNOS knock-out mice. Abeta(1-40) administration induced an increase in TNF-alpha expression and oxidative alterations in prefrontal cortex and hippocampus. Likewise, Abeta(1-40) led to activation of both JNK (c-Jun-NH2-terminal kinase)/c-Jun and nuclear factor-kappaB, resulting in iNOS upregulation in both brain structures. The anti-TNF-alpha antibody reduced all of the molecular and biochemical alterations promoted by Abeta(1-40). These results provide new insights in mouse models of AD, revealing TNF-alpha and iNOS as central mediators of Abeta action. These pathways might be targeted for AD drug development.
Language eng
Pub Type(s) Journal Article
Research Support, Non-U.S. Gov't
PubMed ID 17507561

Role of tumour necrosis factor alpha, but not of cyclo-oxygenase-2-derived eicosanoids, on functional and morphological indices of dystrophic progression in mdx mice: a pharmacological approach.

Editor's note: U.S. patent 6,379,666, issued to Edward Tobinick on April 30, 2002, filed December 11, 2000, details the use of etanercept and other biologic TNF antagonists for the treatment of muscular dystrophy.

Neuropathol Appl Neurobiol. 2007 Jun;33(3):344-59.
Role of tumour necrosis factor alpha, but not of cyclo-oxygenase-2-derived eicosanoids, on functional and morphological indices of dystrophic progression in mdx mice: a pharmacological approach.

Pierno S,
Nico B,
Burdi R,
Liantonio A,
Didonna MP,
Cippone V,
Fraysse B,
Rolland JF,
Mangieri D,
Andreetta F,
Ferro P,
Camerino C,
Zallone A,
Confalonieri P,
De Luca A.
Unit of Pharmacology, Department of Pharmacobiology, Faculty of Pharmacy, University of Bari, Bari, Italy.

The role of tumour necrosis factor (TNF)-alpha or cyclo-oxygenase-2 (COX-2) eicosanoids in dystrophinopathies has been evaluated by chronically treating (4-8 weeks) adult dystrophic mdx mice with the anti-TNF-alpha etanercept (0.5 mg/kg) or the COX-2 inhibitor meloxicam (0.2 mg/kg). Throughout the treatment period the mdx mice underwent a protocol of exercise on treadmill in order to worsen the pathology progression; gastrocnemious muscles from exercised mdx mice showed an intense staining for TNF-alpha by immunohistochemistry. In vivo, etanercept, but not meloxicam, contrasted the exercise-induced forelimb force drop. Electrophysiological recordings ex vivo, showed that etanercept counteracted the decrease in chloride channel function (gCl), a functional index of myofibre damage, in both diaphragm and extensor digitorum longus (EDL) muscle, meloxicam being effective only in EDL muscle. None of the drugs ameliorated calcium homeostasis detected by electrophysiology and/or spectrofluorimetry. Etanercept, more than meloxicam, effectively reduced plasma creatine kinase (CK). Etanercept-treated muscles showed a reduction of connective tissue area and of pro-fibrotic cytokine TGF-beta1 vs. untreated ones; however, the histological profile was weakly ameliorated. In order to better evaluate the impact of etanercept treatment on histology, a 4-week treatment was performed on 2-week-old mdx mice, so to match the first spontaneous degeneration cycle. The histology profile of gastrocnemious was significantly improved with a reduction of degenerating area; however, CK levels were only slightly lower. The present results support a key role of TNF-alpha, but not of COX-2 products, in different phases of dystrophic progression. Anti-TNF-alpha drugs may be useful in combined therapies for Duchenne patients.
PMID: 17493014 [PubMed - in process]

New Anti-TNF Approach for Alzheimer's Disease - New Patent Issues

New Anti-TNF Approach for Alzheimer's Disease

Los Angeles, CA (PRWEB) May 8, 2007 -- Increasing scientific evidence supports a central role of TNF-alpha, the "master regulator" of the immune response(1), in the pathogenesis of Alzheimer's Disease(AD)(2-9). TNF-alpha is thought to amplify brain inflammation, and, by so doing, to participate in the process whereby AD attacks thinking and memory)(2-17). Excess TNF-alpha has been demonstrated in AD, in both the cerebrospinal fluid(18) and the blood(19, 20).

New U.S. patent 7214658, issued today, describes a novel approach to AD. Rather than directly attacking amyloid, an approach which has frustrated scientists for decades, this new approach attacks excess TNF-alpha.

"Attacking excess TNF-alpha has proven to be a breakthrough for the treatment of a variety of diseases, such as rheumatoid arthritis and ankylosing spondylitis, where TNF-alpha is known to be elevated. Since excess TNF-alpha has now been shown to be present in AD it makes eminent sense to investigate an anti-TNF approach for Alzheimer's Disease," stated Edward Tobinick, MD, the inventor of this new approach and Medical Director of the Institute for Neurological Research (INR), a private medical group, inc. in Los Angeles. Further information is available on the website of the INR, at www.nrimed.com.

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19. Zuliani, G., et al., Plasma cytokines profile in older subjects with late onset Alzheimer's disease or vascular dementia. J Psychiatr Res, 2007 Oct; 41(8): 686-93. Epub 2006 Apr 4.
20. Alvarez, A., et al., Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in Alzheimer disease. Neurobiol Aging, 2007 Apr; 28(4):533-6.

Association of Tumor Necrosis Factor Polymorphisms with Guillain-Barré Syndrome.

Title Association of Tumor Necrosis Factor Polymorphisms with Guillain-Barré Syndrome.
Author(s) Zhang J, Dong H, Li B, Li CY, Guo L
Institution Second Hospital of Hebei Medical University, Shijiazhuang, PR China.
Source Eur Neurol 2007 May 4; 58(1) :21-25.
Abstract It has been reported that the tumor necrosis factor (TNF)alpha promoter polymorphism is associated with autoimmune disease and inflammatory disease. It has also been claimed that this polymorphism may affect TNFalpha expression. We investigated the TNFalpha -308 polymorphism and TNFalpha levels in 79 unrelated Chinese patients with Guillain-Barré syndrome (GBS) and 78 healthy controls using PCR-RFLP and ELISA assay. Patients with GBS were divided into 2 subgroups, acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and acute motor axonal neuropathy (AMAN), based on electrophysiological information. We found that the TNFalpha2 allele was associated with increased risk of GBS (OR = 1.876, 95% CI = 1.144-3.075, p = 0.008), particularly for AMAN, the main subtype (OR = 2.914, 95% CI = 1.412-6.015, p = 0.004), but there was no association between TNFalpha polymorphism and AIDP. We also found that carriers of the TNFalpha2 allele had significantly higher TNFalpha2 levels than TNFalpha1 homozygotes (p < 0.05). These data indicate that TNFalpha promoter polymorphism is responsible for susceptibility to GBS, especially to AMAN. The TNFalpha2 allele is associated with higher levels of TNFalpha. Copyright (c) 2007 S. Karger AG, Basel.
Language ENG
Pub Type(s) JOURNAL ARTICLE
PubMed ID 17483581