K252a, a high-affinity nerve growth factor receptor blocker, improves psoriasis: an in vivo study using the severe combined immunodeficient mouse-human skin model.
The peripheral nervous system, in addition to its sensory and motor functions, can induce a local inflammatory response known as neurogenic inflammation. This phenomenon plays a critical role in several inflammatory diseases, e.g., asthma, atopy, rheumatoid arthritis, psoriasis, and ulcerative colitis. Neurogenic inflammation and the role of nerve growth factor (NGF) have been extensively studied in psoriasis. There are increased levels of NGF in the keratinocytes and upregulation of NGF receptor (NGF-R) in the cutaneous nerves of psoriatic plaques. NGF can influence all the salient pathologic events noticed in psoriasis such as proliferation of keratinocytes, angiogenesis, T cell activation, expression of adhesion molecules, proliferation of cutaneous nerves, and upregulation of neuropeptides. In this double-blinded, placebo-controlled study, we addressed the role of NGF/NGF-R in psoriasis in an in vivo system using the severe combined immunodeficient (SCID) mouse-human skin model of psoriasis. The transplanted psoriatic plaques on the SCID mice (n=12) were treated with K252a, a high-affinity NGF receptor blocker. Psoriasis significantly improved following 2 wk of therapy. The length of the rete pegs changed from 308.57+/-98.72 to 164.64+/-46.78 microm (p<0.01, Student's t test). A similar improvement of psoriasis was observed by directly inhibiting NGF with NGF-neutralizing antibody. NGF-neutralizing antibody in normal saline at 10 ng (n=4) and 20 ng (n=4) per kilogram of body weight doses were used. Both doses of NGF-neutralizing antibody reduced rete peg lengths significantly, e.g., from 298.5+/-42.69 to 150.52+/-32.93 microm (p<0.05, Student's t test). This study provides evidence for the role of NGF and its high-affinity receptor in the pathogenesis of psoriasis and insights to develop novel therapeutic modalities.
Raychaudhuri
Siba P
SP
Psoriasis Research Institute, Palo Alto, California, USA.
Sanyal
Mrinmoy
M
Weltman
Helena
H
Kundu-Raychaudhuri
Smriti
S
D000818:Animals; D002227:Carbazoles / Q000627:therapeutic use*; D002455:Cell Division; D004195:Disease Models, Animal; D006801:Humans; D026121:Indole Alkaloids; D015603:Keratinocytes / Q000502:physiology; D051379:Mice; D016513:Mice, SCID; D020932:Nerve Growth Factor / Q000502:physiology; D009416:Nerve Regeneration / Q000187:drug effects; D011565:Psoriasis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D020800:Receptor, Nerve Growth Factor / Q000037:antagonists & inhibitors*; D020917:Receptor, trkA / Q000502:physiology
D002227:Carbazoles; D026121:Indole Alkaloids; D020800:Receptor, Nerve Growth Factor; D020932:Nerve Growth Factor; C049985:staurosporine aglycone; D020917:Receptor, trkA