Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria and as antinflammatory drug.
Chloroquine at neutral pH is not protonated and enters the cell by simple diffusion, and diffuses to acid vacuoles too. At acid pH (pH 4.7) CQ, that is a weak base, becomes protonated to CQ2+ that cannot leave by diffusion the vacuole anymore.
In the presence of CQ therefore the pH of acid vesicles increases and many of their functions are impaired (endosomes, lysosomes, Golgi)
The antimalarial drugs quinine, chloroquine and mefloquine are antagonists at 5-HT3 receptors BJPOpen 2007
- For most of the last century drugs such as quinine, chloroquine and mefloquine (Lariam) have provided a safe, cheap and effective method of controlling malaria. The antimalarial properties of these compounds are thought to be a consequence of inhibiting parasite growth within infected erythrocytes. However, there are a growing number of clinical reports that show these drugs may also have neurological side effects, including paranoia, anxiety and depression. Emerging experimental evidence supports the hypothesis that these compounds adversely affect transmission at both neuromuscular junctions and synapses.
Mefloquine selectively increases asynchronous acetylcholine release from motor nerve terminals. 2006
McArdle JJ, Sellin LC, Coakley KM, Potian JG, Hognason K.
Neuropharmacology. 2006 Mar;50(3):345-53. Epub 2005 Nov 9.PMID: 16288931
Clin Pharmacol Ther. 1997 Jun;61(6):677-83.
Chloroquine-induced venodilation in human hand veins.
Abiose AK, Grossmann M, Tangphao O, Hoffman BB, Blaschke TF.
Division of Clinical Pharmacology, Stanford University School of Medicine, CA 94305-5113, USA.
OBJECTIVE: Hypotension induced by parenteral administration of chloroquine is a common and serious adverse effect of this drug. Our aim was to investigate whether chloroquine produces venodilation in vivo and to explore the underlying mechanisms. METHODS: Vascular effects of chloroquine were studied in healthy volunteers with use of the dorsal hand vein technique at the Geriatric Research Education and Clinical Center, Veterans Affairs Palo Alto Health Care System. We studied 22 healthy volunteers (19 men and three women). Venous responsiveness was determined with the dorsal hand vein technique, which measures the diameter of the vein. RESULTS: Chloroquine was found to produce a dose-dependent relaxation of hand veins preconstricted with the alpha 1-receptor selective agonist phenylephrine. The venodilatory response to chloroquine ranged from 15% +/- 19% at an infusion rate of 0.75 microgram/min to 61% +/- 24% at 48 microgram/min. Venodilation was attenuated by the nitric-oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) so that the dose of chloroquine required to produce 20% venodilation was increased from 3.7 micrograms/min to 15 micrograms/min (p < 0.01). In the presence of a combination of histamine receptor antagonists, there was also a diminution of the vasodilatory response to chloroquine from 72% +/- 5% to 44% +/- 5% at the infusion rate of 96 micrograms/min. The response was further reduced to 33% +/- 7% by the coinfusion of H1-/H2-receptor antagonists with L-NMMA. CONCLUSION: Chloroquine produces venodilation at infusion rates that achieve local concentrations likely similar to those observed systemically after clinically relevant intravenous doses. The date also suggest a role for nitric oxide and histamine release in mediating this response.
CQ and Nitric Oxide
Papers chloroquine nitric oxide
Chloroquine-Induced Nitric Oxide: New Treatment for an Emerging Epidemic of Obesity-Related Glomerulopathy
To cite this article:
M.M. Osman, A. Khalil, M.H. Ahmed.
Diabetes Technology & Therapeutics. December 2006, 8(6): 691-692. doi:10.1089/dia.2006.8.691. PMID: 17109602
Toxicol Lett. 2008 Apr 21;178(1):52-60. Epub 2008 Feb 15.
Chloroquine-induced nitric oxide increase and cell death is dependent on cellular GSH depletion in A172 human glioblastoma cells.
Park BC, Park SH, Paek SH, Park SY, Kwak MK, Choi HG, Yong CS, Yoo BK, Kim JA.
College of Pharmacy, Yeungnam University, Gyeongsan 712-749, South Korea.
Chloroquine (CQ) is used to treat malaria and a variety of inflammatory diseases including systemic lupus erythematosus and rheumatoid arthritis. However, CQ is known to cause cytotoxicity of which mechanism is still uncertain. This study investigated the molecular mechanism responsible for the cell death in CQ-treated A172 human glioblastoma cells. CQ-induced apoptotic cell death of the cells in a time- and concentration-dependent manner. CQ also increased the production of nitric oxide in the cells. However, the pretreatment with aminoguanidine (AG) and N-Omega-nitro-l-arginine methyl ester (NAME), nitric oxide synthase inhibitors, did not block the CQ-induced cell death. In contrast to NO level increase, the level of intracellular reactive oxygen species (ROS) and their extracellular release were transiently and mildly increased by CQ. In addition, CQ depleted cellular GSH content, which was accompanied with time-dependent increase in GSH peroxidase without any significant change in GSH reductase activity. Glutathione (GSH) S-transferase activity was only transiently increased at 15 min treatment with CQ. Furthermore, the CQ-induced cell death was significantly suppressed when intracellular GSH decrease was prevented by the pretreatment with N-acetylcysteine (NAC) or glutathione ethylester (GSH-EE). At the same time, the pretreatment of the cells with NAC and GSH-EE significantly blocked the CQ-induced NO increase, representing that CQ-induced NO increase was resulted from the depletion of GSH. CQ also induced time-dependent increase in Bax level and caspase-3 activity with no change in Bcl-2 level. Overall, these results suggest that CQ-induced NO increase and cell death are dependent on GSH depletion, the cellular redox changes.
Nitric oxide might be involved in the chloroquine-improved insulin sensitivity: old treatment for global danger.
Diabetes Res Clin Pract. 2006 Apr;72(1):110-1. Epub 2005 Oct 26.
In vitro evidence of the inhibitory capacity of chloroquine on arginase activity in sickle erythrocytes. 2007
Iyamu EW, Ekekezie C, Woods GM.
Br J Haematol. 2007 Oct;139(2):337-43.
CQ and ATM (ataxia telangiectasia)
ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome. 2006
Schneider JG, Finck BN, Ren J, Standley KN, Takagi M, Maclean KH, Bernal-Mizrachi C, Muslin AJ, Kastan MB, Semenkovich CF.
Cell Metab. 2006 Nov;4(5):377-89.
* Cell Metab. 2006 Nov;4(5):337-8.
Metabolic syndrome is associated with insulin resistance and atherosclerosis. Here, we show that deficiency of one or two alleles of ATM, the protein mutated in the cancer-prone disease ataxia telangiectasia, worsens features of the metabolic syndrome, increases insulin resistance, and accelerates atherosclerosis in apoE-/- mice. Transplantation with ATM-/- as compared to ATM+/+ bone marrow increased vascular disease. Jun N-terminal kinase (JNK) activity was increased in ATM-deficient cells. Treatment of ATM+/+apoE-/- mice with low-dose chloroquine, an ATM activator, decreased atherosclerosis. In an ATM-dependent manner, chloroquine decreased macrophage JNK activity, decreased macrophage lipoprotein lipase activity (a proatherogenic consequence of JNK activation), decreased blood pressure, and improved glucose tolerance. Chloroquine also improved metabolic abnormalities in ob/ob and db/db mice. These results suggest that ATM-dependent stress pathways mediate susceptibility to the metabolic syndrome and that chloroquine or related agents promoting ATM activity could modulate insulin resistance and decrease vascular disease.
CQ and Calcium Influx
Arch Int Pharmacodyn Ther. 1986 Apr;280(2):254-63.
Mechanism of chloroquine-induced inhibition of smooth muscle contraction.
Ebeigbe AB, Aloamaka CP, Alohan FI.
The study was designed to characterize the mechanism of chloroquine-induced depression of contractility in isolated rat ileal smooth muscle. Chloroquine (10(-7)-10(-4) M) depressed both spontaneous as well as 10(-7) M acetylcholine-induced contractions dose-dependently. The decline in contractile responses to maximal dose of Ach (10(-6) M) in Ca-free medium was significantly increased by treatment with chloroquine. Restoration of Ca++ to Ach-stimulated "Ca-depleted" tissues produced contractions due to Ca++ influx; these contractions were prevented by chloroquine, dose-dependently. Using "Ca-loading" and "Ca-washing" procedures 10(-6) M Ach was observed to mobilize Ca++ from a "membrane-bound" pool, perhaps containing residual Ca++ of extracellular origin. Chloroquine significantly inhibited the rate of filling of such "membrane-bound" pool. The results show that chloroquine-induced depression of mechanical activity of the rat ileal smooth muscle is associated with diminished Ca++ influx, as well as impaired mobilization of Ca++ from an Ach-sensitive "membrane-bound" pool.
CQ and hormones activity
Endocrinology. 1992 Dec;131(6):2622-8.
Correlation of follicle-stimulating hormone (FSH)-receptor complex internalization with the sustained phase of FSH-induced calcium uptake by cultured rat Sertoli cells.
Grasso P, Santa-Coloma TA, Reichert LE Jr.
Department of Biochemistry and Molecular Biology, Albany Medical College, New York 12208.
We have previously reported that synthetic peptide amides corresponding to regions of the beta-subunit of human FSH [hFSH-beta-(1-15) and hFSH-beta-(51-65)] have the ability to bind calcium and to facilitate its entry into liposomes. In the present study, we have examined the ability of synthetic peptides corresponding to the entire primary structure of hFSH-beta-subunit, to induce calcium influx in cultured rat Sertoli cells. Calcium (as 45Ca2+) uptake in response to 50 microM hFSH-beta-(1-15), hFSH-beta-(21-35), or hFSH-beta-(51-65) peptide amides was 2.5-, 2.4-, and 2.0-fold higher, respectively, than basal uptake. Pretreatment of Sertoli cells for 5 min with phenylarsine oxide (PAO, 80 microM), an inhibitor of receptor-mediated endocytosis, significantly (P < 0.05) reduced 45Ca2+ influx in response to hFSH-beta-(1-15), hFSH-beta-(21-35), and hFSH-beta-(51-65). A delay of 20 min was required, however, before the inhibitory effect of PAO on 45Ca2+ uptake was observed. Specific binding of [125I] hFSH to receptor at 4 C was unaffected by PAO. After 2 h at 37 C, however, approximately 1.6-fold more [125I]hFSH specifically bound at 4 C could be dissociated from the cell surfaces of PAO-pretreated Sertoli cell monolayers, compared to untreated monolayers. This result is consistent with an inhibitory effect of PAO on FSH receptor internalization. Chloroquine (at 100 microM), a lysosomotropic agent known to block FSH degradation, also significantly (P < 0.05) inhibited FSH-induced 45Ca2+ uptake. Extending our earlier studies, these results suggest that the sustained (> 20 min) phase of FSH-induced calcium uptake, also seen in response to synthetic hFSH-beta-(1-15), hFSH-beta-(21-35), and hFSH-beta-(51-65) peptide amides, may occur as a consequence of FSH-receptor complex internalization and FSH degradation. Vesicular uptake of extracellular calcium, which accompanies internalization of FSH-receptor complexes, and release of channel-forming peptides by lysosomal hydrolysis of FSH suggests a novel mechanism whereby FSH increases intracellular calcium levels in Sertoli cells.
Ultrastructural basis for chloroquine-induced increase in intracellular insulin in adipocytes: alteration of lysosomal function.
Smith RM, Jarett L.
Proc Natl Acad Sci U S A. 1982 Dec;79(23):7302-6.
A quantitative morphological analysis of insulin uptake into adipocytes was undertaken to determine the structural basis for chloroquine-induced increases in intracellular insulin. Adipocytes were incubated with ferritin-labeled insulin in the presence or absence of 50 microM chloroquine at 37 degrees C for 2-90 min and the uptake of the hormone conjugate was determined quantitatively. Quantitative morphometry of cellular organelles also was performed.
Chloroquine treatment of adipocytes incubated with 70 nM ferritin-labeled insulin resulted in:
- a 120% increase in the number of lysosomes in the cytoplasm;
- a 75% increase in the average concentration of ferritin-labeled insulin in a lysosome;
- a 25% increase in the percentage of lysosomes containing ferritin-labeled insulin.
The cumulative result of these effects was a substantial increase in the amount of intact intracellular hormone within the lysosomes. These morphological data are consistent with biochemical data concerning chloroquine-induced accumulation of 125I-labeled insulin in adipocytes.