Potent mammalian cerebroprotection and neuronal cell death inhibition are afforded by a synthetic antioxidant analogue of marine invertebrate cell protectant ovothiols.
Implicit strategies for neuroprotection in the adult brain include GABAA receptor activation, N-methyl-d-aspartate receptor and sodium voltage-gated channel inhibition. Ironically, these same targets may be harmful to the immature or developing brain. Protection has been demonstrated for both immature and mature brain with the use of a synthetic ovothiol analogue. The following beneficial effects have been demonstrated in mice: protection against audiogenic seizures, brain structures with clear-cut delineation of ibotenate-challenged white and grey matter lesions along with exceptional early and delayed protections, and potent cerebral cell death inhibition. The compound lacks both GABAergic activity and sodium channel blocker properties, which may help explain the lack of toxicity normally expressed in an immature brain utilizing these agents [J.W. Olney (2002) Neurotoxicology, 93, 1-10]. The oxidized form of the compound is virtually devoid of antioxidant activity. In vivo it exhibits cerebroprotective properties similar to those of reduced compounds endowed with antioxidant properties. This unexpected finding has prompted an extensive in vitro exploration of underlying molecular mechanisms that have led to the identification of several recycling mechanisms consistent with non rate-limiting conversion of oxidized to reduced compound forms. Taken as a whole, this work offers an unique combined in vitro and in vivo support that: (i). antioxidant therapy, here engineered from marine invertebrate egg protectants, may be a valuable strategy in protecting both mammalian adult and developing brain; and (ii). recycling (thiol-disulphide exchange) properties of the oxidized form of an antioxidant compound are as important as the antioxidant potential exhibited by a bioactive reduced antioxidant in certain neuroprotective processes.
Vamecq
Joseph
J
INSERM UNIV 045131, Neuropaediatrics Department of Professor Louis Vallée, Salengro University Hospital, CHRU Lille, 59037 Lille, France. lvallee@chru-lille.fr
Maurois
Pierre
P
Bac
Pierre
P
Bailly
Fabrice
F
Bernier
Jean-Luc
JL
Stables
James P
JP
Husson
Isabelle
I
Gressens
Pierre
P
D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D001562:Benzimidazoles / Q000633:toxicity; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D001930:Brain Injuries / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020195:Epilepsy, Reflex / Q000188:drug therapy*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005526:Food, Formulated / Q000009:adverse effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D007051:Ibotenic Acid / Q000633:toxicity; D020287:In Situ Nick-End Labeling / Q000379:methods; D066298:In Vitro Techniques; D008275:Magnesium Deficiency; D008762:Methylhistidines / Q000032:analysis / Q000737:chemistry / Q000627:therapeutic use*; D051379:Mice; D008815:Mice, Inbred Strains; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010084:Oxidation-Reduction; D011748:Pyrogallol / Q000378:metabolism; D011767:Pyruvate Decarboxylase / Q000378:metabolism; D011897:Random Allocation; D012399:Rotation; D013879:Thioredoxins / Q000378:metabolism; D013997:Time Factors
D001562:Benzimidazoles; D018690:Excitatory Amino Acid Agonists; D008762:Methylhistidines; D018696:Neuroprotective Agents; C434503:mercaptobenzimidazol; D011748:Pyrogallol; C050085:ovothiol C; D007051:Ibotenic Acid; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D011767:Pyruvate Decarboxylase