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Targeting IKK2 by pharmacological inhibitor AS602868 prevents excitotoxic injury to neurons and oligodendrocytes

  • Basic Neurosciences, Genetics and Immunology - Original Article
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Abstract

Among the diverse mechanisms involved in the pathophysiology of post-ischemic and post-traumatic injuries, excitotoxicity and nuclear factor-κB (NF-κB) activation through induction of IκB 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-κB activity. Our results suggest that AS602868 may prove to be a valuable approach in treating neurodegeneration and demyelination associated with cerebral trauma and ischemia.

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Acknowledgments

The authors are most grateful to Michel Dreano for the scientific input during the project. This work was supported by grants from Serono International SA, Italian Ministry of Education, University and Scientific Research-PRIN 2004, 2005 and 2006; Centre of Study and Research on Aging, Brescia; MIUR Centre of Excellence for Innovative Diagnostics and Therapeutics (IDET) of Brescia University.

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Authors and Affiliations

  1. Division of Pharmacology and Experimental Therapeutics, Department of Biomedical Sciences and Biotechnologies, School of Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy

    I. Sarnico, F. Boroni, M. Benarese, M. Alghisi, A. Valerio, P. Spano & M. Pizzi

  2. Istituto Ricovero e Cura a Carattere Scientifico, S. Camillo Hospital, 30100, Venice, Italy

    L. Battistin & P. Spano

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  1. I. Sarnico
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  2. F. Boroni
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  3. M. Benarese
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  4. M. Alghisi
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  5. A. Valerio
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  7. P. Spano
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Correspondence to M. Pizzi.

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Sarnico, I., Boroni, F., Benarese, M. et al. Targeting IKK2 by pharmacological inhibitor AS602868 prevents excitotoxic injury to neurons and oligodendrocytes. J Neural Transm 115, 693–701 (2008). https://doi.org/10.1007/s00702-007-0016-1

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  • DOI: https://doi.org/10.1007/s00702-007-0016-1

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