Date Published:
2014 Dec

Publication Type:
Journal Article

Authors:

W. Wrasidlo
L.A. Crews
I.F. Tsigelny
E. Stocking
V.L. Kouznetsova
D. Price
A. Paulino
T. Gonzales
C.R. Overk
C. Patrick
E. Rockenstein
E. Masliah

Secondary:
Br J Pharmacol

Volume:
171

Pagination:
5757-73

Issue:
24

PMID:
25117211

URL:
https://pubmed.ncbi.nlm.nih.gov/25117211

DOI:
10.1111/bph.12875

Keywords:
AIDS Dementia Complex;Animals;Antineoplastic Agents;Cyclin-dependent kinase 5;Dasatinib;Erlotinib Hydrochloride;Flavonoids;HIV Envelope Protein gp120;In Vitro Techniques;Indoles;Internal;Lapatinib;Mice;Mice, Transgenic;Neurodegenerative Diseases;Neurons;Neuroprotective Agents;Protein Kinase Inhibitors;Purines;Pyrimidines;Pyrroles;Quinazolines;Rats;Roscovitine;Sunitinib;Thiazoles

Abstract:
<p>BACKGROUND AND PURPOSE: Anti-retrovirals have improved and extended the life expectancy of patients with HIV. However, as this population ages, the prevalence of cognitive changes is increasing. Aberrant activation of kinases, such as receptor tyrosine kinases (RTKs) and cyclin-dependent kinase 5 (CDK5), play a role in the mechanisms of HIV neurotoxicity. Inhibitors of CDK5, such as roscovitine, have neuroprotective effects; however, CNS penetration is low. Interestingly, tyrosine kinase inhibitors (TKIs) display some CDK inhibitory activity and ability to cross the blood-brain barrier.EXPERIMENTAL APPROACH: We screened a small group of known TKIs for a candidate with additional CDK5 inhibitory activity and tested the efficacy of the candidate in in vitro and in vivo models of HIV-gp120 neurotoxicity.KEY RESULTS: Among 12 different compounds, sunitinib inhibited CDK5 with an IC50 of 4.2 μM. In silico analysis revealed that, similarly to roscovitine, sunitinib fitted 6 of 10 features of the CDK5 pharmacophore. In a cell-based model, sunitinib reduced CDK5 phosphorylation (pCDK5), calpain-dependent p35/p25 conversion and protected neuronal cells from the toxic effects of gp120. In glial fibrillary acidic protein-gp120 transgenic (tg) mice, sunitinib reduced levels of pCDK5, p35/p25 and phosphorylated tau protein, along with amelioration of the neurodegenerative pathology.CONCLUSIONS AND IMPLICATIONS: Compounds such as sunitinib with dual kinase inhibitory activity could ameliorate the cognitive impairment associated with chronic HIV infection of the CNS. Moreover, repositioning existing low MW compounds holds promise for the treatment of patients with neurodegenerative disorders.</p>