MINOCYCLINE MAY IMPROVE FUNCTIONAL OUTCOME AFTER ACUTE ISCHEMIC STROKE

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Minocycline and stroke

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The benefit of treatment with tPA is limited and it has to be administrated within a short time window; furthermore, the side effects are serious including increased risk of subsequent hemorrhagic transformation.

The studies find that the benefit of tPA treatment alone is limited and has serious side effects. While many new agents have been studied to ameliorate this, minocycline, minocycline and stroke, a tetracycline antibiotic, seems the most promising.

Some investigators have suggested that administration of minocycline may be suitable as a general treatment of patients minocycline and stroke acute stroke that is safe and can be used in both ischemic and hemorrhagic strokes as a single treatment that may provide benefits in minocycline and stroke the deficits from ischemic stokes with little side effects.

Strokes are a cause of death in western, industrialized countries and are a major cause of long-lasting disability. Approximatelynew and recurrent ischemic or hemorrhagic strokes occurred each year from to in the United States, minocycline and stroke. Of these approximatelywere first events and, were recurrent strokes [1]. More thanischemic strokes have been reported to occur every year in the USA [2]. Stroke is more frequent in men than in women, of all ages, minocycline and stroke.

One of every 19 deaths in the USA is caused by strokes. Thrombolytic therapy of acute ischemic strokes with tPA is the only FDA approved therapy, but because of the adverse side effects from treatment with tPA, many physicians have opted out of treating stroke patients with tPA, minocycline and stroke. Great progress has been lexapro and weight in finding the risk factors for stroke [2,5].

This is only little changed despite the progress in determining the risk factors for ischemic stroke. Control of blood pressure and some supplements such as magnesium have been found to reduce the risk of stroke. Many compounds have been investigated to reduce infarct size and improve neurological outcomes, minocycline and stroke, and some have shown effect in animal models.

Yet, most of these compounds have failed in the transition to clinical, minocycline and stroke to deleterious side effects or an even more limited time window.

Studies have suggested various forms of anti-inflammatory treatments to reduce the deficits from strokes. It is a problem; however, minocycline and stroke inflammation may be both beneficial and destructive depending on the timing of the intervention of the inflammation modulation.

In this review we discuss the use minocycline and stroke a readily available substance, minocycline, for reducing the harm from inflammatory processes that occurs subsequent to the acute phase of an ischemic stroke. This review also discusses the neuroprotective properties of minocycline. The ischemic insult from stroke causes necrotic cell death by changing the balance in pH, nutrition, waste removal, minocycline and stroke, and temperature.

A subsequent ischemic cascade occurs. Immediately after blocking blood minocycline and stroke to a region of the brain a cascade of events occurs, causing cells to rapidly depolarize. Glutamate release leads to calcium influx through NMDA receptors, which in turn leads to excitotoxic cell death. As described by Gotoh et al.

Depolarization waves spread from the infarct core, damaging surrounding cells, eventually involving the penumbra.

There is evidence that the destruction of brain tissue from ischemia somehow causes an immune reaction and that the resulting inflammatory reactions cause some of the acute damage and, in particular, contribute to the progression of the damage that was caused by the initial localized ischemia [8]. This means that treatment that somehow reduces the inflammatory processes induced by activation of the innate or the adaptive immune system might reduce the deficits from strokes.

A review by Wang et al. Reperfusion minocycline and stroke an occluded vessel leads to a generation of reactive oxygen species ROS. ROS then stimulate ischemic cells to secrete inflammatory cytokines and chemokines that upregulate adhesion molecules and peripheral leukocyte recruitment, respectively [9]. Activated inflammatory cells also release more cytokines, matrix metalloproteinases MMPsnitric oxide, and more ROS.

Secretion of Minocycline and stroke lead to blood-brain barrier disruption, which exacerbates the injury through involvement of activated microglia and involved peripheral inflammatory cells, minocycline and stroke. Importantly though, Wang [10] concluded that while inflammation is an important mediator in the pathology of ischemic stroke, inflammation may play both beneficial and detrimental role: Wang [10] in suggested that early inflammatory responses may potentiate injury while later responses might be important in recovery and repair.

The only FDA approved treatment of acute strokes is thrombolytic therapy using minocycline and stroke plasminogen activator tPA which has a limited time window for administration [11], and its beneficial effect is limited. Therefore considerable experience of its use has been gained. It increases the risk of bleeding and can therefore not be used in treatment labor plans and incentive scheme hemorrhagic stroke, and treatment of ischemic stroke with tPA may cause transformation into hemorrhagic stroke.

Therefore, tPA cannot be administrated before it is ruled out that the stroke is not a hemorrhagic stroke. Consequently, a CT minocycline and stroke be performed, minocycline and stroke, which delays therapy with tPA.

A minocycline and stroke history of recent brain trauma or surgeries, bleeding problems, uncontrolled high blood pressure or use minocycline and stroke blood thinners rules out tPA use. Due to the nature of hospital organization, these studies may take several hours.

Add to this the time it takes for a person to reach the hospital, several hours can elapse before treatment can be made. The upper time limit for delay from the occurrence of a stroke and the administration of tPA is regarded to be 3 to 4. The study did concede though that giving tPA in acute ischemic stroke within the first minutes did not yield a statistically significant benefit in the first 24 hours and even increased the risk of hemorrhagic stroke.

To override this limiting effect, intravenous tPA is administered. Minocycline is a semisynthetic drug that has been in minocycline and stroke since the s. It is in the tetracycline family of antibiotics, which were discovered in by Duggar [18] as a natural product of Streptomyces.

Streptomyces are soil-dwelling bacteria that produce tetracycline among other diverse products. Modifications to the chemically isolated byproducts eventually led to two of the more common semi-synthetic tetracycline used clinically today as antibiotics, minocycline and stroke, doxycycline and minocycline.

In order to exert this activity, tetracycline inhibits protein translation by binding to the P30 subunit of the ribosome. Minocycline is distinguishable from other tetracycline for its highly lipophilic nature; it is a superior blood-brain barrier penetrator compared to the other tetracycline, including doxycycline [19].

It has properties, discussed below, that are outside of its antibiotic abilities. Minocycline has been shown to alter many cellular processes that may have beneficial relevance to stroke recovery. Programmed cell death, or apoptosis, is largely mediated by caspases. The two pathways of caspase activation, extrinsic and intrinsic, are named after the source of the stress to the cell.

In the intrinsic pathway, different variables inevitably lead to mitochondrial outer membrane permeabilization, causing decreased ATP production, and further release of proteins that lead to caspase activation. The Bcl-2 family of proteins is involved in the pathway of intrinsic activation; however, there are pro-apoptotic and anti-apoptotic members of this family.

By inducing anti-apoptotic Bcl-2 proteins and inhibiting cytochrome c release, minocycline has been shown to protect kidney epithelial cells at the mitochondrial level [23]. Minocycline and stroke showed similar results in neurons but not astrocytesas well as improved stroke-induced behavioral effects and cerebral infarction areas, but showed a dose-dependent effect in that high doses exacerbated ischemic injury [24].

The initial occlusion of a blood vessel in ischemic stroke damages tissue by inadequate perfusion. When blood flow is reestablished, either spontaneously or by therapeutic intervention, the affected tissue may undergo reperfusion injury.

This is associated with deleterious effects in both stroke and myocardial infarctions [25]. The surge of oxygen into these injured tissues leads to generation of reactive oxygen species ROS. This, in turn, causes mitochondrial permeability transition which leads to mitochondrial depolarization and swelling, along with outer membrane rupture which leads to cytochrome c release and subsequent activation of caspases to end in cell death.

Minocycline is a known inhibitor of microglial activity in the brain [27], minocycline and stroke. Early research showed that minocycline prevented the excitotoxin-induced proliferation of microglia [28].

Minocycline also reduced the microglia-induced cell death of endothelial cells and astrocytes by half [29]. MMP-2 has been shown to play a role in early blood-brain barrier disruption [31].

Furthermore, minocycline and stroke, direct injection of MMP-2 onto the rodent brain disrupts the blood-brain barrier [32]. Animal models have shown that MMP-9 is actively induced following ischemia, and is localized to endothelial cells and parenchymal cells.

Knockout or inhibition of MMP-9 has been shown to decrease lesion volume [33]. MMP-9 levels are higher in brain minocycline and stroke in both human ischemic and hemorrhagic stroke cases [37], minocycline and stroke. Intraperitoneal treatments of minocycline in rats significantly reduced activity minocycline and stroke protein concentration of both MMP-2 and MMP-9, and MMP-9 was extremely sensitive even at low doses [38].

Neuroprotection is the term used for actions that protect the integrity of the central nervous system in cases of ischemic damage such as from ischemic stokes of other forms of trauma [39]. In the first of their studies, they found that minocycline was neuroprotective in a model of global ischemia [41]. In the second, minocycline was shown to reduce infarct volume when given before and after transient middle cerebral artery occlusion MCAO [40]. Treatment with minocycline is different from treatment with tPA.

It does not affect coagulations and it can therefore be administered without ensuring that the patient does not have a hemorrhagic stroke. It is an antibiotic of the tetracycline family and its beneficial effect for stroke is related to its anti-inflammatory and neuroprotective action.

Minocycline it minocycline and stroke not approved for treatment by FDA for treatment of stroke. It can minocycline and stroke used as an "off-label" treatment. There is conflicting data on the use of minocycline in hemorrhagic stroke, minocycline and stroke. In one study, minocycline was found to reduce MMP levels, especially MMP, and some positive behavioral outcomes on days 7 and 28 after stroke [42], minocycline and stroke.

A more recent study found that while minocycline did suppress microglial and macrophage activation in peri-infarct region, there was no reduction in infarct volume or functional benefit on days 5 or 14 post-intracerebral hemorrhage [43]. Minocycline can be used without adverse side effects in the acute stroke period and perhaps throughout the subsequent recovery period. Early research has shown that acute administration of minocycline up to 5 hours after ischemic insult reduces infarct size and inflammation in animal models [44].

Another study correlated these minocycline and stroke in human trials, finding that minocycline was effective at reducing infarct size when administered 5 hours after ischemic insult [21]. On a longer time scale, two studies found that minocycline improved neurological functioning and behavioral recovery when given for four days after ischemic insult in MCAO rodent model and then for four weeks [45].

In the second animal study [46], minocycline did not reduce infarct size, but did decrease the number of activated microglia while preserving plasticity in the dentate gyrus. Recently published clinical trials varied on whether they gave minocycline orally or intravenously, the dose used, and how often minocycline was administered.

InSaivin and Houin [19] described the pharmacokinetics of minocycline. The steady state concentration achieved when this dose is split in half and given orally is 1. As aforementioned, minocycline is highly lipophilic and penetrates the blood-brain barrier well.

As such, the CSF concentration is approximately 0. In humans, the half-life is approximately 24 hours [21], while in rats; it is 3 hours [47]. When taken chronically, patients taking above mg daily commonly complained of dizziness [48]. From a tolerability standpoint, there is no issue for its use as an acute ischemic stroke therapy. There are currently five published clinical trials evaluating the use of minocycline in acute ischemic stroke in order of publication date:

 

Minocycline and stroke

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