The neuroprotective effect of intranasally applied leptin against hypoxic neuronal injury.
Hypoxia may result from hypoperfusion, as seen in the cardio-respiratory arrest. Subsequent to the acute neuronal damage, the delayed neuronal death ensues, and further neurons die within hours or days thereafter. An effective neuroprotective therapeutic agent should counteract one or, ideally, all well-established neuronal death pathways, i.e., excitotoxicity, oxidative stress and apoptosis. All these three mechanisms propagate through distinctive and mutual exclusive signal transduction pathway and contribute to the neuronal loss following the initial hypoxic-ischemic brain injury. Thus, the ideal therapeutic intervention against the hypoxic-ischemic neuronal injury should aim to prevent all three mechanisms of the neuronal death in a concerted effort. Recent studies demonstrated that intranasally administered leptin results in supra-physiological leptin levels at various regions of the brain (including hippocampus) within 30min of administration. We consider leptin to be an ideal neuroprotective agent, having targeted excitotoxicity (directly, by inhibiting AMDA and NMDA) oxidative stress (indirectly, by HIF1 mediation) and apoptosis (directly, by activating ERK 1/2 pathway) and hypothesize that intranasally administered leptin has neuroprotective effect against the neuronal hypoxic injury. If our hypothesis is confirmed, leptin administered before and/or soon after hypoxic injury, may be effective in minimizing the devastating sequelae of such event.
Minciu Macrea
Madalina
M
Salem VA Medical Center, Salem, VA, USA. Madalina.Macrea@va.gov
Misra
Hara
H
Zagrean
Leon
L
D000281:Administration, Intranasal; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018846:Excitatory Amino Acids / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D002534:Hypoxia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020738:Leptin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008959:Models, Neurological; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018384:Oxidative Stress / Q000187:drug effects
D018846:Excitatory Amino Acids; D020738:Leptin; D018696:Neuroprotective Agents