Neurology.
2007 Oct 2;69(14):1404-10
Minocycline treatment in acute
stroke: an open-label, evaluator-blinded study.
Lampl Y, Boaz
M, Gilad R, Lorberboym M, Dabby R, Rapoport A, Anca-Hershkowitz M, Sadeh M.
Department of
Neurology,
BACKGROUND: Ischemic animal model
studies have shown a neuroprotective effect of minocycline. OBJECTIVE: To analyze the effect of minocycline treatment in human acute ischemic stroke.
METHODS: We performed an open-label, evaluator-blinded study. Minocycline at a dosage of 200 mg was administered orally
for 5 days. The therapeutic window of time was 6 to 24 hours after onset of
stroke. Data from NIH Stroke Scale (NIHSS), modified Rankin Scale (mRS), and Barthel Index (BI) were
evaluated. The primary objective was to compare changes from baseline to day 90
in NIHSS in the minocycline group vs
placebo. RESULTS: One hundred fifty-two patients were included in the study.
Seventy-four patients received minocycline treatment,
and 77 received placebo. NIHSS and mRS were
significantly lower and BI scores were significantly higher in minocycline-treated patients. This pattern was already
apparent on day 7 and day 30 of follow-up. Deaths, myocardial infarctions,
recurrent strokes, and hemorrhagic transformations during follow-up did not
differ by treatment group. CONCLUSIONS:
Patients with acute stroke had significantly better outcome with minocycline treatment compared with placebo. The findings
suggest a potential benefit of minocycline in acute
ischemic stroke.
PMID: 17909152 [PubMed
- in process]
Exp Neurol. 2007 Mar;204(1):433-42.
Epub 2007 Jan 17
Differential neuroprotective
effects of a minocycline-based drug cocktail in
transient and permanent focal cerebral ischemia.
Faculty of
Medicine,
Considering that several pathways
leading to cell death are activated in cerebral ischemia, we tested in mouse
models of transient and permanent ischemia a drug cocktail aiming at distinct
pharmacological targets during the evolution of ischemic injury. It consists of
minocycline--an antibiotic with anti-inflammatory
properties, riluzole--a glutamate antagonist, and nimodipine--a blocker of voltage-gated calcium channels.
Administered 2 h after transient or permanent MCAO, it significantly decreased
the size of infarction, by approximately 65% after transient and approximately
35% after permanent ischemia and markedly improve clinical recovery of mice. In
both experimental models a three-drug cocktail achieved significantly more
efficient neuroprotection than any of the components
tested alone. However, some interesting observation emerged from the
single-drug studies. Treatment with minocycline alone was efficient in both experimental models
while treatment with glutamate antagonist riluzole
conferred neuroprotection only after transient MCAO. Immunohistochemical analysis following three-drug treatment
revealed reduced microglia/macrophages and caspase-3
activation as well as preserved GFAP immunoreactivity
following transient ischemia. No detectable differences in the levels of Mac-2,
GFAP and caspase-3 immunoreactivities were observed
72 h after permanent MCAO. These marked differences in the brain tissue
responses to ischemic injury and to treatments suggest that different
pathological mechanisms may be operating in transient and permanent ischemia.
However, the three-drug cocktail exerted significant neuroprotection
in both experimental models thus demonstrating that simultaneous targeting of
several pathophysiological pathways involved in the
evolution of ischemic injury may represent a rational therapeutic strategy for
stroke.
PMID: 17234187 [PubMed
- indexed for MEDLINE]
Stroke.
2007 Jan;38(1):146-52. Epub
2006 Nov 22
Chronic treatment with minocycline
preserves adult new neurons and reduces functional impairment after focal
cerebral ischemia.
Liu
Z, Fan
Y, Won
SJ, Neumann
M, Hu D, Zhou
L, Weinstein
PR, Liu
J.
Department of
Neurological Surgery,
BACKGROUND AND PURPOSE: Evidence
suggests that activated microglia
are detrimental to the survival of new hippocampal
neurons, whereas blocking inflammation has been shown to restore hippocampal neurogenesis after
cranial irradiation and seizure. The aim of this current study is to determine
the effect of minocycline on neurogenesis
and functional recovery after cerebral focal ischemia. METHODS: Four days after
temporary middle cerebral artery occlusion, minocycline
was administered intraperitoneally for 4 weeks. BrdU was given on days 4 to 7 after middle cerebral artery
occlusion to track cell proliferation. The number of remaining new neurons and
activated microglia were quantified in the dentate gyrus. Infarct volume was measured to assess the treatment
effect of minocycline. Motor and cognitive functions
were evaluated 6 weeks after middle cerebral artery occlusion. RESULTS: Minocycline delivered 4 days after middle cerebral artery
occlusion for 4 weeks did not result in reduction in infarct size but
significantly decreased the number of activated microglia
in the dentate gyrus. Minocycline
also significantly increased the number of newborn neurons that coexpressing BrdU and NeuN without significantly affecting progenitor cell
proliferation in the dentate gyrus. Lastly, minocycline significantly improved motor coordination on
the rotor rod, reduced the preferential use of the unaffected limb during
exploration, reduced the frequency of footfalls in the affected limb when
traversing on a horizontal ladder, and improved spatial learning and memory in
the water maze test. CONCLUSIONS: Minocycline reduces functional impairment caused by
cerebral focal ischemia. The improved function is associated with enhanced neurogenesis and reduced microglia
activation in the dentate gyrus and possibly improved
neural environment after chronic treatment with minocycline.
PMID: 17122429 [PubMed
- indexed for MEDLINE]