| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Dermatology Department, Shiraz University of Medical Sciences, Shiraz, Iran
1Correspondence: P.O. Box 71955-687, Shiraz, Iran. E-mail: namazi_mr{at}yahoo.com
ABSTRACT
Psoriasis is an inflammatory disorder characterized by a T helper type 1 cell cytokine pattern. Increased expression of adhesion molecules, prominent neutrophil accumulation, and increased production of nitric oxide are characteristics of this disorder. Moreover, histamine and proteases are supposed to participate in the pathogenesis of psoriasis. Nicotinamide is an inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1) that, through enhancement of nuclear kappa B-mediated transcription, plays a pivotal role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and inflammatory mediators. Through interaction with CD38 and inhibition of IL-1, IL-12, and TNF-
production, nicotinamide produces a mild TH2 bias. Nicotinamide is a potent phosphodiesterase inhibitor and suppresses neutrophil chemotaxis and mast cell histamine release. It inhibits nitric oxide synthase mRNA induction and suppresses antigen-induced lymphocyte transformation. Nicotinamide increases the biosynthesis of ceramides, which upon degradation produce sphingosine. Sphingosine inhibits protein kinase C (PKC) and decreases basal cell proliferation dependent on PKC. Taken together, it can be reasoned that nicotinamide could be a useful addition to anti-psoriatic armamentarium. The combination of nicotinamide and thalidomide or methotrexate provided a powerful synergistic inhibition of murine collagen-induced arthritis. Nicotinamide decreased the methotrexate-induced hepatotoxicity. The above combinations may prove to have a powerful anti-psoriatic effect as well. As PARP inhibitors could exert anti-retroviral effect, nicotinamide could also be of special value in the treatment of HIV-infected psoriatics.—Namazi, M. R. Nicotinamide: a potential addition to the anti-psoriatic weaponry.
Key Words: AIDS • interleukin 12 • nicotinamide • PARP • psoriasis • protein kinase C • T helper cell • treatment • tumor necrosis factor-alpha
BRIEF REVIEW OF THE IMMUNOPATHOGENESIS OF PSORIASIS RELATING TO THE HYPOTHESIS
PSORIASIS is believed to be characterized by a T helper type 1 cell cytokine pattern; IFN-gamma, TNF-, IL-2, and IL-1 are predominantly expressed in this disorder (1)
. This maturation pathway is stimulated by IL-12 released from activated dendritic cells and by exposure of T cells to type 1 cytokines during maturation (2)
. Presentation of antigen by antigen-presenting cells (APCs) to CD4 T lymphocytes leads to lymphocyte transformation and the synthesis of cytokines. The released cytokines stimulate keratinocyte proliferation and the expression of adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), by endothelial cells and keratinocytes. The expression of adhesion molecules allows the infiltration of leukocytes into the lesions (1)
. Chronic lesions of psoriasis vulgaris contain prominent neutrophil accumulations (2)
.
IFN-gamma and TNF- are potent inducers of ICAM-1, CD40, and MHC-II proteins on epidermal keratinocytes, whereas IFN-gamma serves as a potent stimulator of TNF- release from dermal macrophages or monocytes (2)
.
Nitric oxide synthesis is indeed increased in psoriasis (3)
. The production of nitric oxide is 
10-fold higher in nonlesional skin of psoriatics and 10-fold higher again in the plaques themselves (4)
. These observations are highly suggestive of a role for nitric oxide in the development of psoriasis. It has been proposed that nitric oxide may induce the psoriatic disease process at least partly through increment of the release and actions of calcitonin gene-related peptide and substance P, which are considered to play important roles in the pathomechanism of psoriasis by inducing the production of adhesion molecules, keratinocyte hyperproliferation, mast cell degranulation, vasodilation, and chemotaxis of neutrophils (5)
.
The demonstration of increased activity of proteases, such as human leukocyte elastase, in lesions of psoriasis has implicated this system as a potential mediator of many of the abnormal findings in psoriasis. Proteases have the ability to generate inflammatory mediators via the complement cascade (6
, 7)
.
Histamine is also supposed to play a role in the pathogenesis of psoriasis and some observations suggest that skin mast cells in active psoriasis are functionally hyper-reactive. Both cyclosporin A and methotrexate, which are powerful antipsoriatic agents, are potent inhibitors of histamine release (8)
.
Much literature has been generated on the possible role of cyclic nucleotides in psoriasis. It now appears that the mediator system, cyclic AMP-cyclic-GMP as an off-on system, is not as simple as once perceived and cAMP can either stimulate or inhibit cell proliferation (8)
. However, the phosphodiesterase inhibitors aminophylline (9)
and theophylline (10)
, which increase cAMP levels, have been shown to be of benefit in the treatment of psoriasis.
BRIEF REVIEW OF THE PHARMACOLOGY OF NICOTINAMIDE AND THE HYPOTHESIS
Nicotinamide, also known as niacinamide, is the pyridin-3-carboxylic acid amide of niacin, a component of the vitamin B complex. This agent has no effect on blood pressure, pulse, or body temperature (11)
.
Nicotinamide possesses a myriad of effects that make it a potential treatment for psoriasis:
It is an inhibitor of poly (ADP-ribose) polymerase-1 (PARP-1) that functions as a DNA nick-sensor enzyme and contributes to DNA repair and, if overactivated, to cell dysfunction or necrosis. PARP enhances nuclear factor kappa B-mediated transcription, which plays a central role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and inflammatory mediators (12)
.
Nicotinamide has been shown to be capable of inhibition of the expression of ICAM-1 (13)
and MHC-II (14)
and the production of IL-12, TNF- (15)
, and IL-1 (16)
. It interacts with glycosylphosphatidyl-inositol-anchored ADP-ribosyl transferases. These enzymes occur on the outer membrane of lymphocytes. The best known is CD38. Antibodies to CD38 potentiate many biological activities of lymphocytes, particularly in promoting B cell differentiation (16)
. This effect, accompanying the inhibitory effect of nicotinamide on IFN-gamma-induced macrophage activation (14)
and IL-1, IL-12, and TNF- production, results in a mild TH2 bias. This explains why this agent is effective in preventing destructive insulitis, which is characterized by a TH1 bias (16)
.
Moreover, nicotinamide has been reported to exert its anti-inflammatory action partly through suppression of neutrophil chemotaxis (16)
, as also seen in a mouse arthritis model (17)
.
Though nicotinamide is able to scavenge oxygen radicals, it does not scavenge nitric oxide (16)
. However, nicotinamide inhibits nitric oxide synthase mRNA induction in activated macrophages (14)
.
Nicotinamide increases the biosynthesis of ceramides by keratinocytes (18)
. It is known that the sphingosine derived from degradation of surface ceramide inhibits protein kinase C (PKC) and decreases basal cell proliferation dependent on PKC (19)
.
Some studies have shown that transient increases in ceramide levels are associated with the induction of keratinocyte apoptosis (20
, 21)
. This effect could offset the anti-apoptotic effect of nicotinamide exerted through PARP inhibition (16)
.
Nicotinamide has been shown to be capable of suppression of antigen-induced lymphocyte transformation (22)
.
Nicotinamide has been used to reduce the onset of the disease in murine models of arthritis. It not only prevented the development of arthritis, but also inhibited the progress of established collagen-induced arthritis (12
, 23)
. The combined application of thalidomide, an inhibitor of TNF- and cellular immune reactions also used in the treatment of psoriasis (24)
, and nicotinamide provided a powerful synergistic inhibition of arthritis (23)
. The combination of nicotinamide and thalidomide or other TNF- inhibitors may exert a powerful anti-psoriatic effect as well.
Nicotinamide has been shown to enhance the effect of methotrexate on murine models of collagen-induced arthritis (25)
while decreasing the hepatotoxicity of methotrexate (26)
. The nicotinamide-methotrexate combination may prove to be superior to methotrexate alone in the treatment of psoriasis as well.
Niacinamide has been shown to be a potent inhibitor of cAMP phosphodiesterase and to stabilize mast cells and leukocytes, thereby exerting considerable protease- and histamine-release blocking activity (27
, 28)
. As mentioned previously, histamine and proteases are supposed to take part in the pathogenesis of psoriasis.
Taken together, it could be reasoned that nicotinamide could be a useful addition to anti-psoriatic weaponry. An increasing body of evidence suggests the involvement of PARP in HIV infection, as the integration of the viral double-stranded DNA into the host genome requires nicking of both DNA strands and may lead to PARP activation (12)
. Therefore, nicotinamide could be of special value in the treatment of HIV-infected psoriatics, for whom the routine immunosuppressives are contraindicated.
ACKNOWLEDGMENTS
This paper is dedicated to my professor, Dr. F. Hadjani, for his support, kindness, and modesty.
Received for publication January 27, 2003. Accepted for publication April 11, 2003.
REFERENCES
This article has been cited by other articles:
|
|
 |
|
  T. L. Thai, S. K. Fellner, and W. J. Arendshorst ADP-ribosyl cyclase and ryanodine receptor activity contribute to basal renal vasomotor tone and agonist-induced renal vasoconstriction in vivo Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1107 - F1114. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
