title: Agonists at the serotonin receptor (5-HT(1A)) protect the retina from severe photo-oxidative stress.
abstract: OBJECTIVE
  5-HT(1A) agonists are neuroprotective in CNS injury models. The authors evaluated the efficacy of 5-HT(1A) agonists to protect the retina from severe blue light-induced photo-oxidative damage.
  
  
  METHODS
  Albino rats were dosed (subcutaneously) with AL-8309A, 8-OH DPAT, or buspirone once or three times before 6-hour exposure to blue light. Electroretinograms (ERGs) were measured to assess retinal function, and retinal damage was evaluated by light microscopy. Topical ocular dosing with 1.75% AL-8309B was also evaluated. Rats were dosed with WAY-100635, a 5-HT(1A) antagonist, to determine whether protection required activation of the 5-HT(1A) receptor.
  
  
  RESULTS
  ERG response amplitudes were significantly (P < 0.05) depressed more than 66% in vehicle-dosed rats after light exposure. ERGs were significantly higher in rats treated with AL-8309A (0.1-30 mg/kg), 8-OH DPAT (0.1-1 mg/kg), buspirone (5-20 mg/kg) or topical ocular with 1.75% AL-8309B. Retinas from AL-8309A and 8-OH DPAT-treated rats were devoid of histologic lesions. Significant protection was measured in rats dosed once 0, 24, or 48 hours before light exposure. Protection provided by dosing with AL-8309B or 8-OH DPAT was inhibited in rats predosed with WAY-100635.
  
  
  CONCLUSIONS
  5-HT(1A) agonists provided potent and complete functional and structural protection. Protection was inhibited by treatment with WAY-100635, confirming the requirement for activating the 5-HT(1A) receptor in initiating this survival pathway. Single-dose experiments with AL-8309A suggest that the mechanism of protection is rapidly activated and protection persists for 48 hours. AL-8309B (1.75%) was effective after topical ocular dosing. AL-8309B is under evaluation in the clinic and may be useful in treating age-related macular degeneration.
authors.affiliation: Alcon Research, Ltd., Fort Worth, Texas 76134-2099, USA. robert.collier@alconlabs.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Collier
authors.forename: Yamini
authors.initials: Y
authors.lastname: Patel
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Martin
authors.forename: Olga
authors.initials: O
authors.lastname: Dembinska
authors.forename: Mark
authors.initials: M
authors.lastname: Hellberg
authors.forename: D Scott
authors.initials: DS
authors.lastname: Krueger
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kapin
authors.forename: Carmelo
authors.initials: C
authors.lastname: Romano
mesh_terms: D000818:Animals; D002065:Buspirone / Q000494:pharmacology; D003623:Dark Adaptation; D004305:Dose-Response Relationship, Drug; D004596:Electroretinography; D008027:Light; D008297:Male; D018384:Oxidative Stress; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011833:Radiation Injuries, Experimental / Q000209:etiology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000528:radiation effects*; D012162:Retinal Degeneration / Q000209:etiology / Q000517:prevention & control*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology
chemical_list: D010879:Piperazines; D011725:Pyridines; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D002065:Buspirone