Minocycline may widen window for treatment of ischemic stroke
October 16, 2007 |
Drug seems to help patients who are seen after tPA no longer an option
HOLON, ISRAEL | In a randomized trial, patients treated with minocycline within 24 hours of ischemic stroke onset had significantly better outcomes than those treated with placebo.
If the results of the study are confirmed, minocycline may provide an additional treatment to tissue plasminogen activator (tPA), but with a wider time window for treatment.
An open-label, evaluator-blinded study published in Neurology on Oct. 2 compared outcomes in 74 acute ischemic stroke patients treated with 200 mg minocycline daily for five days, with outcomes in 77 patients who were treated with a placebo. All patients presented within six to 24 hours of stroke onset (that is, after the therapeutic window for tPA had ended).
Patients were assessed at seven days, 30 days and 90 days for global functioning, disability and neurologic deficit using the Barthel Index, the modified Rankin Scale and the National Institutes of Health Stroke Scale.
The patients in the minocycline group had significantly better scores on all three measurements at every followup interval (see table), compared with the placebo group. There were no significant differences between the two groups in incidence of recurrent stroke, hemorrhagic transformation, myocardial infarction or death.
Although minocycline has shown neuroprotective effects in animal models of neurologic conditions such as Parkinson¹s disease and multiple sclerosis, study author Dr. Yair Lampl of the department of neurology at Edith Wolfson Medical Centre in Holon, Israel, said the mechanism for its effects can only be hypothesized.
³There are studies showing an effect of minocycline on the apoptotic pathway as well as on the inflammatory mechanisms,² Dr. Lampl told the Medical Post via e-mail. ³In animal stroke model studies, a significant effect was found as well. I think that minocycline can influence the late mechanisms of stroke, not the early one on the Œischemic penumbra.¹ ²
However, Dr. Lampl noted that although minocycline could potentially provide a treatment for stroke patients even after the tPA window has closed, time remains a crucial element in stroke treatment.
³It does not change the very important determination that Œtime is brain,¹ and that we have to do our best to reach the hospital during the first three hours,² Dr. Lampl said.
[ cave note-- sorry for the funny characters. It's the way I received it. Also missing is the PubMed # or url]
http://www.blackwell-synergy.com/doi/ab ... 04.02796.x
Minocycline has been shown to have remarkably neuroprotective qualities, but underlying mechanisms remain elusive. We reported here the robust neuroprotection by minocycline against glutamate-induced apoptosis through regulations of p38 and Akt pathways. Pre-treatment of cerebellar granule neurons (CGNs) with minocycline (10–100 µm) elicited a dose-dependent reduction of glutamate excitotoxicity and blocked glutamate-induced nuclear condensation and DNA fragmentations.
Using patch-clamping and fluorescence Ca2+ imaging techniques, it was found that minocycline neither blocked NMDA receptors, nor reduced glutamate-caused rises in intracellular Ca2+.
Instead, confirmed by immunoblots, minocycline in vivo and in vitro was shown to directly inhibit the activation of p38 caused by glutamate. A p38-specific inhibitor, SB203580, also attenuated glutamate excitotoxicity. Furthermore, the neuroprotective effects of minocycline were blocked by phosphatidylinositol 3-kinase (PI3-K) !
inhibitors LY294002 and wortmannin, while pharmacologic inhibition of glycogen synthase kinase 3β (GSK3β) attenuated glutamate-induced apoptosis.
In addition, immunoblots revealed that minocycline reversed the suppression of phosphorylated Akt and GSK3β caused by glutamate, as were abolished by PI3-K inhibitors. These results demonstrate that minocycline prevents glutamate-induced apoptosis in CGNs by directly inhibiting p38 activity and maintaining the activation of PI3-K/Akt pathway, which offers a novel modality as to how the drug exerts protective effects.
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