MAPK signal transduction underlying brain inflammation and gliosis as therapeutic target.
A majority, if not all, acute and progressive neurodegenerative diseases are accompanied by local microglia-mediated inflammation, astrogliosis, infiltration of immune cells, and activation of the adaptive immunity. These processes progress by the expression of cytokines, adhesion molecules, proteases, and other inflammation mediators. In response to brain injury or infection, intracellular signaling pathways are activated in microglia, which turn on inflammatory and antigen-presenting cell functions. Different extrinsic signals shape microglial activation toward neuroprotective or neurotoxic phenotype under pathological conditions. This review discusses recent advances regarding molecular mechanisms of inflammatory signal transduction in neurological disorders and in in vitro models of inflammation/gliosis. Mitogen-activated protein kinases (MAPKs) are a family of serine/threonine protein kinases responsible for most cellular responses to cytokines and external stress signals and crucial for regulation of the production of inflammation mediators. Increased activity of MAPKs in activated microglia and astrocytes, and their regulatory role in the synthesis of inflammatory cytokines mediators, make them potential targets for novel therapeutics. MAPK inhibitors emerge as attractive anti-inflammatory drugs, because they are capable of reducing both the synthesis of inflammation mediators at multiple levels and are effective in blocking inflammatory cytokine signaling. Small molecule inhibitors targeting of p38 MAPK and JNK pathways have been developed and offer a great potential as potent modulators of brain inflammation and gliosis in neurological disorders, where cytokine overproduction contributes to disease progression. Many of the pharmacological MAPK inhibitors can be administered orally and initial results show therapeutic benefits in preclinical animal models.
Kaminska
Bozena
B
Laboratory of Transcription Regulation, Nencki Institute of Experimental Biology, 3 Pasteur Str., Warsaw, Poland. bozenakk@nencki.gov.pl
Gozdz
Agata
A
Zawadzka
Malgorzata
M
Ellert-Miklaszewska
Aleksandra
A
Lipko
Maciej
M
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D005911:Gliosis / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D009457:Neuroglia / Q000187:drug effects / Q000201:enzymology
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors