vinaxanthone and Disease-Models--Animal

Dry eye disease (DED) is a common disorder causing discomfort and ocular fatigue. Corneal nerves are compromised in DED, which may further cause loss of corneal sensation and decreased tear secretion. Semaphorin 3A (Sema3A) is expressed by the corneal epithelium under stress, and is known as an inhibitor of axonal regeneration. Using a murine dry eye model, we found that topical SM-345431, a selective Sema3A inhibitor, preserved corneal sensitivity (2.3 ± 0.3 mm versus 1.4 ± 0.1 mm in vehicle control, p = 0.004) and tear volume (1.1 ± 0.1 mm versus 0.3 ± 0.1 mm in vehicle control, p < 0.001). Fluorescein staining area of the cornea due to damage to barrier function was also reduced (4.1 ± 0.9% in SM-345431 group versus 12.9 ± 2.2% in vehicle control, p < 0.001). The incidence of corneal epithelial erosions was significantly suppressed by SM-345431 (none in SM-345431 group versus six (21%) in vehicle control, p = 0.01). Furthermore, sub-epithelial corneal nerve density and intraepithelial expression of transient receptor potential vanilloid receptor 1 (TRPV1) were significantly preserved with SM-345431. Our results suggest that inhibition of Sema3A may be an effective therapy for DED.

Topics: Animals; Cornea; Corneal Injuries; Disease Models, Animal; Dry Eye Syndromes; Epithelium, Corneal; Gene Expression Regulation; Humans; Mice; Semaphorin-3A; Tears; TRPV Cation Channels; Xanthones

The natural product vinaxanthone has demonstrated a remarkable capability to promote nerve growth following injury or transplantation. In rats following total transection of the spinal cord delivery of vinaxanthone enhanced axonal regeneration, remyelination and angiogenesis at the site of injury all leading to an improved reinstatement of motor function. Through the development of a new ynone coupling reaction, chemically edited derivatives of vinaxanthone have been prepared and studied for improved activity. The coupling reaction allows rapid access to new derivatives, wherein n ynone precursors provide n(2) vinaxanthone analogues. These compounds have been tested for their ability to promote neuronal regrowth using laser axotomy, severing axonal connections in Caenorhabditis elegans. This precise microsurgery using C. elegans allows a new in vivo approach for medicinal chemistry based optimization of neuronal growth promoting compounds.

Topics: Animals; Axons; Caenorhabditis elegans; Chromones; Dimerization; Disease Models, Animal; Dose-Response Relationship, Drug; Lasers; Microsurgery; Molecular Structure; Nerve Regeneration; Neuroprotective Agents; Water; Xanthones