Mefloquine neurotoxicity is mediated by non-receptor tyrosine kinase.
Among several available antimalarial drugs, mefloquine has proven to be effective against drug-resistant Plasmodium falciparum and remains the drug of choice for both therapy and chemoprophylaxis. However, mefloquine is known to cause adverse neurological and/or psychiatric symptoms, which offset its therapeutic advantage. The exact mechanisms leading to the adverse neurological effects of mefloquine are poorly defined. Alterations in neurotransmitter release and calcium homeostasis, the inhibition of cholinesterases and the interaction with adenosine A(2A) receptors have been hypothesized to play prominent roles in mediating the deleterious effects of this drug. Our recent data have established that mefloquine can also trigger oxidative damage and subsequent neurodegeneration in rat cortical primary neurons. Furthermore, we have utilized a system biology-centered approach and have constructed a pathway model of cellular responses to mefloquine, identifying non-receptor tyrosine kinase 2 (Pyk2) as a critical target in mediating mefloquine neurotoxicity. In this study, we sought to establish an experimental validation of Pyk2 using gene-silencing techniques (siRNA). We have examined whether the downregulation of Pyk2 in primary rat cortical neurons alters mefloquine neurotoxicity by evaluating cell viability, apoptosis and oxidative stress. Results from our study have confirmed that mefloquine neurotoxicity is associated with apoptotic response and oxidative injury, and we have demonstrated that mefloquine affects primary rat cortical neurons, at least in part, via Pyk2. The implication of these findings may prove beneficial in suppressing the neurological side effects of mefloquine and developing effective therapeutic modalities to offset its adverse effects.
Department of Pediatrics, Division of Clinical Pharmacology and Toxicology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. dejan.milatovic@vanderbilt.edu
Dejan
D
Milatovic
Jerry W
JW
Jenkins
Jonathan E
JE
Hood
Yingchun
Y
Yu
Lu
L
Rongzhu
Michael
M
Aschner
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D015767:Mefloquine / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D053634:TYK2 Kinase / Q000502:physiology*
D053634:TYK2 Kinase; D015767:Mefloquine
Genomics. 2005 Nov;86(5):539-50
16109470
J Pharmacol Exp Ther. 2006 Jun;317(3):1155-60
16501066
J Biol Chem. 2007 Mar 30;282(13):10104-10116
17283076
Malar J. 2008 Feb 11;7:30
18267019
Acta Trop. 2002 Feb;81(2):167-73
11801224
Neuropharmacology. 2005 Dec;49(8):1132-9
16081111
J Neuroinflammation. 2004 Oct 21;1(1):20
15498098
Mol Cell Neurosci. 2007 Mar;34(3):355-65
17188509
Antimicrob Agents Chemother. 2006 Mar;50(3):1045-53
16495267
J Neurosci. 2002 Jul 1;22(13):5452-61
12097497
Neurology. 2003 Dec 9;61(11 Suppl 6):S101-6
14663021
Travel Med Infect Dis. 2009 Jan;7(1):2-6
19174293
Nature. 1996 Oct 10;383(6600):547-50
8849729
Free Radic Biol Med. 1991;10(3-4):195-200
1907587
J Cell Sci. 2007 Sep 1;120(Pt 17):3034-44
17684059
Clin Exp Pharmacol Physiol. 1985 Sep-Oct;12(5):527-31
3878759
Clin Pharmacol Ther. 1999 Nov;66(5):472-84
10579474
Science. 1996 Aug 9;273(5276):792-4
8670418
Mol Brain. 2010 Jan 21;3:4
20180987
J Neurobiol. 1994 Mar;25(3):294-303
7910846
Neuroscience. 1998 Sep;86(1):279-90
9692761
J Biol Chem. 1999 Jul 23;274(30):20989-96
10409647
Malar J. 2003 Jun 12;2:14
12848898
J Biol Chem. 2004 Dec 17;279(51):53516-23
15322113
Front Biosci. 2003 May 01;8:s676-82
12700130
J Neurochem. 2003 Dec;87(6):1518-26
14713307
Cancer Res. 1986 Dec;46(12 Pt 1):6105-10
3779630
Am J Physiol Cell Physiol. 2002 Apr;282(4):C754-61
11880263
Nature. 1995 Aug 31;376(6543):737-45
7544443
Trends Neurosci. 1999 Jun;22(6):257-63
10354603
J Biol Chem. 1996 Nov 15;271(46):28942-6
8910543
J Pharmacol Exp Ther. 2000 Oct;295(1):29-36
10991957
Neurotoxicology. 2010 Sep;31(5):518-23
20562019
Cell Signal. 2000 Mar;12(3):123-33
10704819
Antimicrob Agents Chemother. 2004 Jul;48(7):2624-32
15215119
Clin Infect Dis. 2001 Oct 1;33(7):1015-21
11528574
J Leukoc Biol. 2010 Mar;87(3):415-23
19955209
Brain Res. 2005 Mar 10;1037(1-2):90-8
15777756
J Cell Biol. 1997 Oct 20;139(2):529-39
9334354
J Biol Chem. 2005 Jan 7;280(1):660-8
15537634
Br J Pharmacol. 2000 Oct;131(4):756-60
11030725
Curr Protoc Toxicol. 2009 Feb;Chapter 12:Unit12.14
20191108
Eur J Pharm Sci. 2007 Oct;32(2):123-7
17698330
Neuron. 2001 Feb;29(2):485-96
11239437
Ann N Y Acad Sci. 1994 Nov 15;744:237-42
7825845