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Calpain Inhibition: A Prospective Th...

Smith, Amena Weston.

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Calpain Inhibition: A Prospective Therapy To Improve Visual Function In Optic Neuritis.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Calpain Inhibition: A Prospective Therapy To Improve Visual Function In Optic Neuritis./
作者:	Smith, Amena Weston.
面頁冊數:	231 p.
附註:	Source: Dissertation Abstracts International, Volume: 74-04(E), Section: B.
Contained By:	Dissertation Abstracts International74-04B(E).
標題:	Biology, Neuroscience. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3533529
ISBN:	9781267777256

Calpain Inhibition: A Prospective Therapy To Improve Visual Function In Optic Neuritis.
Smith, Amena Weston.

Calpain Inhibition: A Prospective Therapy To Improve Visual Function In Optic Neuritis. - 231 p.

Source: Dissertation Abstracts International, Volume: 74-04(E), Section: B.

Thesis (Ph.D.)--Medical University of South Carolina, 2013.

Optic neuritis (ON), inflammation of the optic nerve, is an autoimmune, demyelinating disease of the CNS. ON is associated with multiple sclerosis (MS), and these diseases can be studied within the animal model experimental autoimmune encephalomyelitis (EAE). Increased expression and activity of calpain, a Ca2+-activated protease, has been detected in the optic nerves of (EAE) rodents and in peripheral blood mononuclear cells (PBMCs) of MS patients. The overall study hypothesis is that calpain activation contributes to the inflammatory, demyelinating and neurodegenerative events of EAE and MS. Furthermore, calpain inhibition will attenuate these events, resulting in histological and functional neuroprotection. Investigation of acute EAE optic nerve and retina revealed increased expression and activity of calpain and associated pro-apoptotic proteins. Moreover, expression of key inflammatory markers and apoptotic death of retinal ganglion cells was increased in EAE-ON retina. Prophylactic treatment of EAE rats with calpain inhibitor markedly attenuated inflammation and apoptosis. Chronic-progressive EAE mice exhibited early, severe losses in the visual acuity of one eye while the other was spared. Therapeutic treatment with calpain inhibitor improved visual acuity, inner retinal function and paralysis, with associated attenuation of histopathology. Furthermore, calpain inhibition dramatically attenuated the proliferative response of lymph node cells isolated from EAE mice. A predominance of Treg and Th2 cytokines with a concurrent decrease in pro-inflammatory IL-17 expression accompanied the reduction in proliferation. Calpain inhibition in vitro downregulated Th1/Th17 pro-inflammatory cytokine expression in MS patient PBMCs. Treatment with calpain inhibitor or exogenous Indoleamine 2, 3-dioxygenase (IDO) suppressed myelin basic protein (MBP)-stimulated T cell proliferation. Interestingly, IDO mRNA expression was low in naive and activated MS PBMCs compared with control PBMCs. Pre-treatment with calpeptin led to an increase in IDO transcription in activated MS PBMCs but not in control cells. Finally, whereas incubation of human neurons in conditioned medium from activated MS PBMCs increased neuronal cell death, incubation in medium from activated, calpeptin-treated PBMCs preserved neuronal viability. In summary, calpain inhibition enhanced survival of retinal neurons and improved visual function in EAE, and promoted an anti-proliferative response in the immune cell milieu of both EAE and MS. Thus, calpain inhibition is an ideal candidate strategy for the protection of vision in MS.

ISBN: 9781267777256Subjects--Topical Terms:

1017680
Biology, Neuroscience.

Calpain Inhibition: A Prospective Therapy To Improve Visual Function In Optic Neuritis.
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