(taken from the application?s abstract): There is increasing evidence that through the release of neuropeptides the cutaneous sensory neurological system plays an important role in the pathogenesis of inflammatory skin disorders. Certain skin diseases such as psoriasis, contact dermatitis and atopic dermatitis may have a significant neurogenic component. The hypothesis to be tested by the proposed research is that certain topically-delivered neuromodulators will prove to be effective therapeutic agents for the treatment of a wide range of inflammatory skin diseases. Thus, the long-term objective is to develop topical agents with novel anti-inflammatory activities. Specifically, agents such as calcitonin-gene-related peptide (CGRP), alpha-melanocyte stimulating hormone (alpha-MSH), substance P receptor (SPR) antagonists such as spantide II (peptide molecule) and SR 140333 (a non-peptide), which have anti-inflammation properties or inhibit various aspects of neurogenic inflammation will be utilized as topical compounds to treat well-defined models of cutaneous inflammation.
The specific aims of this research proposal are:
Aim #1) The preparation of topical formulations (gels, creams and lotions) of neuromodulatory agents using prototype topical vehicles and screening these formulations for antiinflammatory effects in an animal model of cutaneous inflammation. Studies designed under this aim include formulation of topical agents (gels, creams and lotions) of neuromodulators and screening of these formulations for anti-inflammatory activity in a murine contact hypersensitivity model;
Aim #2) The development, evaluation and optimization of various topical neuromodulatory formulations, which have shown promise in Specific Aim #1) Development of topical formulations includes compatibility and stability of neuromodulators in topical vehicles. The stable formulations will be optimized by ex vivo skin absorption and distribution studies in hairless mouse skin using Franz diffusion cells and;
Aim #3) To determine the effectiveness of topically applied neuromodulatory agents to inhibit cutaneous inflammation. This will be accomplished by utilizing well-defined murine models of cutaneous inflammation such as allergic contact dermatitis, irritant contact dermatitis and acute photodermatitis. The effect of topical formulations on cutaneous inflammation will be compared with that of intravenous administration of these peptides. The results of these studies are intended to provide the basic information required for the development of novel skin disorders.
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