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Journal of Clinical Pathology and Laboratory Medicine | Volume 3

July 05-06, 2019 | Paris, France

Pathology and Surgical Pathology

International Conference on

Combinatory FK506 and minocycline treatment alleviates prion-induced

neurodegenerative events via caspase-mediated MAPK-NRF2 pathway

Mazhar Hussain Mangi

Agricultural Univeristy, China

ranscription factors play a significant role during the

symptomatic onset and progression of prion diseases.

We previously showed the immunomodulatory and nuclear

factor of activated T cells’ (NFAT) suppressive effects of an

immunosuppressant, FK506, in the symptomatic stage and

an antibiotic, minocycline, in the pre-symptomatic stage of

prion infection in hamsters. Here we used for the first time,

a combinatory FK506+minocycline treatment to test its

transcriptional modulating effects in the symptomatic stage of

prion infection. Our results indicate that prolonged treatment

withFK506+minocyclinewaseffectiveinalleviatingastrogliosis

andneuronal death triggeredbymisfoldedprions. Specifically,

the combinatory therapy with FK506+minocycline lowered

the expression of the astrocytes activation marker GFAP

and of the microglial activation marker IBA-1, subsequently

reducing the level of pro-inflammatory cytokines interleukin

1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) and

increasing the levels of anti- inflammatory cytokines IL-

10 and IL-27. We further found that FK506+minocycline

treatment inhibitedmitogen-activated protein kinase (MAPK)

p38 phosphorylation, NF-kB nuclear translocation, caspase

expression and enhanced phosphorylated cAMP response

element-binding protein (pCREB) and phosphorylated Bcl2-

associated death promoter (pBAD) levels to reduce cognitive

impairment and apoptosis. Interestingly, FK506+minocycline

reduced mitochondrial fragmentation and promoted

nuclear factor–erythroid2-related factor-2 (NRF2)-heme

oxygenase 1 (HO-1) pathway to enhance survival. Taken

together, our results show that a therapeutic cocktail of

FK506+minocycline is an attractive candidate for prolonged

use in prion diseases and we encourage its further clinical

development as a possible treatment for this disease.