title: Safety and efficacy evaluation of carnosine, an endogenous neuroprotective agent for ischemic stroke.
abstract: OBJECTIVE
  An urgent need exists to develop therapies for stroke that have high efficacy, long therapeutic time windows, and acceptable toxicity. We undertook preclinical investigations of a novel therapeutic approach involving supplementation with carnosine, an endogenous pleiotropic dipeptide.
  
  
  METHODS
  Efficacy and safety of carnosine treatment was evaluated in rat models of permanent or transient middle cerebral artery occlusion. Mechanistic studies used primary neuronal/astrocytic cultures and ex vivo brain homogenates.
  
  
  RESULTS
  Intravenous treatment with carnosine exhibited robust cerebroprotection in a dose-dependent manner, with long clinically relevant therapeutic time windows of 6 hours and 9 hours in transient and permanent models, respectively. Histological outcomes and functional improvements including motor and sensory deficits were sustained on 14th day poststroke onset. In safety and tolerability assessments, carnosine did not exhibit any evidence of adverse effects or toxicity. Moreover, histological evaluation of organs, complete blood count, coagulation tests, and the serum chemistry did not reveal any abnormalities. In primary neuronal cell cultures and ex vivo brain homogenates, carnosine exhibited robust antiexcitotoxic, antioxidant, and mitochondria protecting activity.
  
  
  CONCLUSIONS
  In both permanent and transient ischemic models, carnosine treatment exhibited significant cerebroprotection against histological and functional damage, with wide therapeutic and clinically relevant time windows. Carnosine was well tolerated and exhibited no toxicity. Mechanistic data show that it influences multiple deleterious processes. Taken together, our data suggest that this endogenous pleiotropic dipeptide is a strong candidate for further development as a stroke treatment.
authors.affiliation: Department of Neurology, Salford Royal Hospital, Stott Lane, Salford, England.
authors.forename: Ok-Nam
authors.initials: ON
authors.lastname: Bae
authors.forename: Kelsey
authors.initials: K
authors.lastname: Serfozo
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Baek
authors.forename: Ki Yong
authors.initials: KY
authors.lastname: Lee
authors.forename: Anne
authors.initials: A
authors.lastname: Dorrance
authors.forename: Wilson
authors.initials: W
authors.lastname: Rumbeiha
authors.forename: Scott D
authors.initials: SD
authors.lastname: Fitzgerald
authors.forename: Muhammad U
authors.initials: MU
authors.lastname: Farooq
authors.forename: Bharath
authors.initials: B
authors.lastname: Naravelta
authors.forename: Archit
authors.initials: A
authors.lastname: Bhatt
authors.forename: Arshad
authors.initials: A
authors.lastname: Majid
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D002336:Carnosine / Q000008:administration & dosage* / Q000009:adverse effects*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007262:Infusions, Intravenous; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D020521:Stroke / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D018696:Neuroprotective Agents; D002336:Carnosine