Improving outcomes of neuroprotection by minocycline: guides from cell culture and intracerebral hemorrhage in mice.
Minocycline ameliorates deficits in models of acute and chronic neurological diseases, but many publications do not replicate these results. We tested the hypothesis that a key factor in achieving neurological benefits is the exposure of neural cells to local high concentrations of minocycline. This hypothesis was evaluated by using human neurons in culture and in a mouse model of intracerebral hemorrhage (ICH). In culture, neurons were very vulnerable to blood-induced toxicity, with 60% lost within 24 hours in an environment of 5% blood in culture medium. Minocycline reduced blood-induced neurotoxicity in a concentration-dependent manner. In vivo, the introduction of blood into the striatum of mice to simulate ICH resulted in a massive lesion by 24 hours. When minocycline was mixed with the blood used to inflict ICH, the resulting extent of neuropathology was significantly less than that achieved with intraperitoneal administration of medication. The combination of intracerebral and intraperitoneal minocycline improved neuroprotection compared with either alone. We then delayed minocycline treatment and injected it into the hematoma 1 hour after ICH. We found greater alleviation of brain damage and neuronal death with increasing concentrations of minocycline injected locally, which was reflected in limited behavioral and histological recovery. We conclude that the prospect of neuroprotection with minocycline is improved by high concentrations of minocycline delivered locally into the central nervous system with supplementation from systemic administration.
Xue
Mengzhou
M
Hotchkiss Brain Institute, Clara Christie Centre for Mouse Genomics and Modelling of Human Disease, Department of Clinical Neurosciences, University of Calgary, 3330 Hospital Drive, Calgary, Alberta T2N 4N1, Canada.
Mikliaeva
Elena I
EI
Casha
Steve
S
Zygun
David
D
Demchuk
Andrew
A
Yong
V Wee
VW
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005780:Gelatin / Q000378:metabolism; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008911:Minocycline / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
D018696:Neuroprotective Agents; D005780:Gelatin; D008911:Minocycline