title: Targeting IKK2 by pharmacological inhibitor AS602868 prevents excitotoxic injury to neurons and oligodendrocytes.
abstract: Among the diverse mechanisms involved in the pathophysiology of post-ischemic and post-traumatic injuries, excitotoxicity and nuclear factor-kappaB (NF-kappaB) activation through induction of IkappaB kinase (IKK) complex have a primary role. We investigated the effects of the selective inhibitor of the IKK2 subunit, the anilinopyrimidine derivative AS602868, on excitotoxic injury produced in rat organotypic hippocampal slices and cerebellar primary neurons. Brief exposure to N-methyl-D-aspartate (NMDA) induces astrocyte reactivity, neuron cell death and oligodendrocyte degeneration in hippocampal slices. Application of AS602868 elicited a long-lasting protection of both neurons and oligodendrocytes. Maximal effect was observed with prolonged application of the compound after NMDA exposure. Neuroprotection was also evident in primary cultures of cerebellar granule cells starting from 20 nM concentration. AS602868-elicited neuroprotection correlated with inhibition of NF-kappaB activity. Our results suggest that AS602868 may prove to be a valuable approach in treating neurodegeneration and demyelination associated with cerebral trauma and ischemia.
authors.affiliation: Division of Pharmacology and Experimental Therapeutics, Department of Biomedical Sciences and Biotechnologies, School of Medicine, University of Brescia, Brescia, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Sarnico
authors.forename: F
authors.initials: F
authors.lastname: Boroni
authors.forename: M
authors.initials: M
authors.lastname: Benarese
authors.forename: M
authors.initials: M
authors.lastname: Alghisi
authors.forename: A
authors.initials: A
authors.lastname: Valerio
authors.forename: L
authors.initials: L
authors.lastname: Battistin
authors.forename: P
authors.initials: P
authors.lastname: Spano
authors.forename: M
authors.initials: M
authors.lastname: Pizzi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D051550:I-kappa B Kinase / Q000378:metabolism*; D066298:In Vitro Techniques; D004676:Myelin Basic Protein / Q000378:metabolism; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009836:Oligodendroglia / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: C519899:AS602868; D018690:Excitatory Amino Acid Agonists; D004676:Myelin Basic Protein; D018696:Neuroprotective Agents; D011743:Pyrimidines; D016202:N-Methylaspartate; D051550:I-kappa B Kinase; C518254:Ikbkb protein, rat