Neuroprotection with the proteasome inhibitor MLN519 in focal ischemic brain injury: relation to nuclear factor kappaB (NF-kappaB), inflammatory gene expression, and leukocyte infiltration.
The ubiquitin proteasome system (UPS) is a major cellular protein degradation pathway that involves the modulation of key proteins controlling inflammation, cell cycle regulation and gene expression. Modulation of the UPS with proteasome inhibitors has indicated efficacy in the treatment of several disease states including cancer and neuro-inflammatory disorders. In particular, a series of recent reports have evaluated the pre-clinical efficacy of the proteasome inhibitor MLN519 for the treatment of focal ischemic/reperfusion brain injury in rats. Evidence from these studies indicate that the neuroprotection provided by MLN519 is related to an anti-inflammatory effect linked to the modulation of nuclear factor kappaB (NF-kappaB) activity, attenuation of cytokine (TNF-alpha, IL-1beta, and IL-6) and cellular adhesion molecule (ICAM-1 and E-selectin) expression, and reduction of neutrophil and macrophage infiltration into the injured rat brain. It is the aim of this paper to review the experimental neuroprotection data reported using MLN519 with a focus on the molecular and cellular mechanisms of anti-inflammatory action.
Williams
Anthony J
AJ
Walter Reed Army Institute of Research, Department of Applied Neurobiology, Silver Spring, MD 20910, United States. anthony.williams@na.amedd.army.mil
Dave
Jitendra R
JR
Tortella
Frank C
FC
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D020520:Brain Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D004660:Encephalitis / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors
D004791:Enzyme Inhibitors; D016328:NF-kappa B; D018696:Neuroprotective Agents; C411422:PS519; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine