Neuroinflammation: friend and foe for ischemic stroke

So it is more difficult to solve that you expected. WHAT THE FUCK IS YOUR STRATEGY TO SOLVE IT? I'm guessing burying your head in the sand because

you are waiting for SOMEONE ELSE TO SOLVE THE PROBLEM. That behavior would get you fired in my book.

Neuroinflammation: friend and foe for ischemic stroke

• Richard L. Jayaraj,
• Sheikh Azimullah,
• Rami Beiram,
• Fakhreya Y. Jalal &
• Gary A. Rosenberg 

Journal of Neuroinflammation volume 16, Article number: 142 (2019) Cite this article

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Abstract

Stroke, the third leading cause of death and disability worldwide, is undergoing a change in perspective with the emergence of new ideas on neurodegeneration. The concept that stroke is a disorder solely of blood vessels has been expanded to include the effects of a detrimental interaction between glia, neurons, vascular cells, and matrix components, which is collectively referred to as the neurovascular unit. Following the acute stroke, the majority of which are ischemic, there is secondary neuroinflammation that both promotes further injury, resulting in cell death, but conversely plays a beneficial role, by promoting recovery. The proinflammatory signals from immune mediators rapidly activate resident cells and influence infiltration of a wide range of inflammatory cells (neutrophils, monocytes/macrophages, different subtypes of T cells, and other inflammatory cells) into the ischemic region exacerbating brain damage. In this review, we discuss how neuroinflammation has both beneficial as well as detrimental roles and recent therapeutic strategies to combat pathological responses. Here, we also focus on time-dependent entry of immune cells to the ischemic area and the impact of other pathological mediators, including oxidative stress, excitotoxicity, matrix metalloproteinases (MMPs), high-mobility group box 1 (HMGB1), arachidonic acid metabolites, mitogen-activated protein kinase (MAPK), and post-translational modifications that could potentially perpetuate ischemic brain damage after the acute injury. Understanding the time-dependent role of inflammatory factors could help in developing new diagnostic, prognostic, and therapeutic neuroprotective strategies for post-stroke inflammation.(What is your strategy for creating these solutions?)

Mechanism of Action and Clinical Potential of Fingolimod for the Treatment of Stroke

Fingolimod already has this positive research needing more followup: Already approved for MS, so your doctor being an innovative sort will likely use this as an off-label use for stroke. That will never occur, you will just need to deal with the fact your doctor is doing nothing in the first week to save all your dying neurons.(neuronal cascade of death)

FTY720 Preserves Blood-Brain Barrier Integrity Following Subarachnoid Hemorrhage in Rats

The latest here:

Mechanism of Action and Clinical Potential of Fingolimod for the Treatment of Stroke

Wentao Li¹, Haoliang Xu² and Fernando D. Testai¹*

• ¹Department of Neurology and Rehabilitation, University of Illinois College of Medicine, Chicago, IL, USA
• ²Department of Pathology, University of Illinois College of Medicine, Chicago, IL, USA

Fingolimod (FTY720) is an orally bio-available immunomodulatory drug currently approved by the FDA for the treatment of multiple sclerosis. Currently, there is a significant interest in the potential benefits of FTY720 on stroke outcomes. FTY720 and the sphingolipid signaling pathway it modulates has a ubiquitous presence in the central nervous system and both rodent models and pilot clinical trials seem to indicate that the drug may improve overall functional recovery in different stroke subtypes. Although the precise mechanisms behind these beneficial effects are yet unclear, there is evidence that FTY720 has a role in regulating cerebrovascular responses, blood–brain barrier permeability, and cell survival in the event of cerebrovascular insult. In this article, we critically review the data obtained from the latest laboratory findings and clinical trials involving both ischemic and hemorrhagic stroke, and attempt to form a cohesive picture of FTY720’s mechanisms of action in stroke.

Introduction

Fingolimod (FTY720) is an orally bio-available immunomodulatory drug unique for its reversible leukocyte sequestration properties. In 2010, it was approved by the FDA for the treatment of multiple sclerosis (MS) (1, 2).

Given the current understanding of the role of the immune system in the pathophysiology of brain injury in cerebrovascular diseases, there is now significant interest in the potential benefits of FTY720 on stroke outcomes. Several groups have independently evaluated its effects in rodent models of brain ischemia and intracerebral hemorrhage (ICH). More recently, pilot clinical trials have been conducted demonstrating promising results, albeit in small populations (3–5). Taken together, these studies seem to indicate that administration of FTY720 results in overall improved functional recovery in different stroke subtypes.

The precise mechanisms behind these beneficial effects are still under investigation. FTY720 is a partial sphingosine-1-phosphate (S1P) agonist with immunomodulatory properties that regulates cerebrovascular responses, blood–brain barrier (BBB) permeability, and central nervous system (CNS) cell survival (6, 7). In this article, we will organize these elements and attempt to form a cohesive picture of FTY720’s mechanisms of action in stroke, and critically review the data obtained from recent clinical trials.

Role of the Immune System in Stroke Progression

Immunomodulation is a well-characterized effect of FTY720 and is thought to mediate some of the beneficial effects seen in stroke models. In order to understand the extent to which the immune system impacts the evolution of stroke outcomes, we will sketch a proposed model of the immune cascade following ischemic insult.

In the immediate aftermath of an ischemic event, complement activation, clot formation, and oxidative stress result in direct damage to local vasculature. Endothelial cells die and detach, interrupting the integrity of the BBB and exposing sub-endothelial antigens. Immune cells adhere to the vessel wall and upregulate the expression of chemoattractant and adhesion molecules that lead to the infiltration of the brain parenchyma by the innate immune system.

A combination of neutrophils, monocytes, and macrophages, this innate immune system further contributes to vascular compromise and early inflammation. One well-documented process is through the release of matrix metalloproteinases (MMPs) by the immune cells, particularly MMP-9, which contributes to the breakdown of the BBB with the resultant edema and growth of the infarcted area (8).

In the parenchyma, glial cells are also activated by the inflammation and damage-associated molecular patterns (DAMPs) released from dying neurons. These reactive astrocytes and microglia further stimulate the recruitment of leukocytes, which release their own pro-inflammatory chemokines, perpetuating a cycle of vascular damage, inflammation, and cell death (9).

The second, adaptive phase of the immune response is mediated predominantly by effector T cells, which are stimulated by DAMPS and brain-specific antigens released upon neuronal cell death (10). These T cells mobilize to the injured regions of the brain, infiltrating a compromised BBB to release pro-inflammatory cytokines, including IFN-γ, resulting in a delayed neurotoxic effect (11, 12). Of note, brain-specific antigens were identified in cervical nodes and palatine tonsils of animals with cerebral ischemia and stroke survivors. Interestingly, some of these antigens were associated with infarct volume and survival. While these studies need to be replicated in larger cohorts, they suggest the participation of peripheral lymphoid tissue in stroke-associated inflammation and outcomes.

Lastly, the inflammatory process is brought to an end via a combination of B cells and regulatory T cells. The latter acts through IL-10, which in combination with TGF-β produced by local macrophages, suppresses further helper T-cell-induced inflammation, and promotes the regeneration of remaining viable neurons (13, 14).

A reduction in various components of the innate and adaptive immune response have been associated with better stroke outcomes. Clinically, a lower ratio of CD14+ pro-inflammatory monocytes to CD16+ reparative monocytes has been correlated with better acute and long-term functional outcomes (15). Similarly, decreased complement activation, specifically the reduced expression of C3, C4, and C-reactive protein, has been associated with better recovery at 3 months post-stroke (16). Experimentally, inhibition of CD8+ and CD4+ T-cell migration into the CNS and direct disruption of CD8+ cytotoxicity has led to reduced infarct volume and post-ischemic inflammation (17). Disruption of the DAMPs-activated γδT cells have also resulted in decreased infarct size and better functional recovery in mice (18). Finally, direct delivery of B cells and IL-10 to the brain in animal models have resulted in a reduction of inflammatory cytokines produced by effector T cells and a reduction of infarct size (19, 20).

Fingolimod and Stroke-Related Mechanisms of Action

Pharmacology

Isaria sinclairii, otherwise known as “winter-insect and summer-plant,” is a fungus that has been used in traditional Chinese medicine for over 300 years. Classically prescribed as a panacea for multiple ailments, it produces an atypical amino acid myriocin (ISP-1) that blocks the synthesis of sphingolipids. This chemical compound has since been modified into fingolimod, also known as FTY720 (21). In Western Medicine, FTY720 initially showed promise in preventing ischemic–reperfusion injury following organ transplant, but failed clinical trials due to the development of acute macular edema in some patients (22, 23). In 2010, it became the first oral disease modifying drug approved for treatment of MS (6). In its base form, FTY720 is an orally bio-available, lipophilic molecule that readily crosses the BBB and steadily accumulates in the CNS white and gray matter (24). It bears a structural similarity to sphingosine and is reversibly phosphorylated primarily by Sphingosine-Kinase 2 (SphK2) and, to a lesser extent, by SphK1 (25). In its activated form, FTY720-phosphate is a sphingosine-1-phosphate (S1P) analog that binds to cell membrane G-coupled S1P receptors (S1PR) S1PR1, 3, 4, and 5, but not S1P2 (26). With the exception of S1PR4, these receptors are ubiquitously distributed in the CNS (Table 1). In addition to its action on cell surface receptors, FTY720 regulates the synthesis of different bioactive sphingolipids and, together with S1P, regulates gene expression via epigenetic mechanisms (Figure 1). The half-life of FTY720 averages ~9 days and its pharmacology is not sensibly affected by age, weight, sex, or ethnicity (27).

Systems Biology of Immunomodulation for Post-Stroke Neuroplasticity: Multimodal Implications of Pharmacotherapy and Neurorehabilitation

Whatever the fuck this means. Written to make sure survivors can't understand. Research like this isn't for survivors anyway, it is for our stroke doctors to implement even though they never read and analyze research for their patients. Someday 1 out of 100,00 doctors will quibble with that gross generalization.
http://journal.frontiersin.org/article/10.3389/fneur.2016.00094/full?utm_source=newsletter&

Mohammed Aftab Alam^†, V. P. Subramanyam Rallabandi^† and Prasun K. Roy*

• National Brain Research Centre, Gurgaon, India

Aims: Recent studies indicate that anti-inflammatory drugs, act as a double-edged sword, not only exacerbating secondary brain injury but also contributing to neurological recovery after stroke. Our aim is to explore whether there is a beneficial role for neuroprotection and functional recovery using anti-inflammatory drug along with neurorehabilitation therapy using transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), so as to improve functional recovery after ischemic stroke.

Methods: We develop a computational systems biology approach from preclinical data, using ordinary differential equations, to study the behavior of both phenotypes of microglia, such as M1 type (pro-inflammatory) vis-à-vis M2 type (anti-inflammatory) under anti-inflammatory drug action (minocycline). We explore whether pharmacological treatment along with cerebral stimulation using tDCS and rTMS is beneficial or not. We utilize the systems pathway analysis of minocycline in nuclear factor kappa beta (NF-κB) signaling and neurorehabilitation therapy using tDCS and rTMS that act through brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) signaling pathways.

Results: We demarcate the role of neuroinflammation and immunomodulation in post-stroke recovery, under minocycline activated-microglia and neuroprotection together with improved neurogenesis, synaptogenesis, and functional recovery under the action of rTMS or tDCS. We elucidate the feasibility of utilizing rTMS/tDCS to increase neuroprotection across the reperfusion stage during minocycline administration. We delineate that the signaling pathways of minocycline by modulation of inflammatory genes in NF-κB and proteins activated by tDCS and rTMS through BDNF, TrkB, and calmodulin kinase (CaMK) signaling. Utilizing systems biology approach, we show that the activation pathways for pharmacotherapy (minocycline) and neurorehabilitation (rTMS applied to ipsilesional cortex and tDCS) results into increased neuronal and synaptic activity that commonly occur through activation of N-methyl-d-aspartate receptors. We construe that considerable additive neuroprotection effect would be obtained and delayed reperfusion injury can be remedied, if one uses multimodal intervention of minocycline together with tDCS and rTMS.

Conclusion: Additive beneficial effect is, thus, noticed for pharmacotherapy along with neurorehabilitation therapy, by maneuvering the dynamics of immunomodulation using anti-inflammatory drug and cerebral stimulation for augmenting the functional recovery after stroke, which may engender clinical applicability for enhancing plasticity, rehabilitation, and neurorestoration.

Introduction

Recent investigations have reported that immune responses to inflammation are non-specific systemic infections associated with progression of neurodegenerative diseases via activation of macrophages (1). Minocycline is a tetracycline antibiotic having several properties, such as anti-inflammatory, anti-apoptosis, free radical scavenger, and protein misfolding (2). The therapeutic effects of minocycline in preclinical models of neurodegenerative diseases showed direct neuroprotection and reduction of microglial inflammatory responses (3). It has been reported in in vivo studies that minocycline blocks the adhesion of leukocytes to cerebrovascular endothelial cells induced by lipopolysaccharides, as well as tumor necrosis factor-α (TNF-α) production in the brain (4). In vitro studies have reported the anti-inflammatory effects of minocycline for neuroprotection (5) and in macrophages (6). Neuroprotective effects of minocycline include reduction of macrophage activation, prevention of the potentiation of ischemia-like injury to astrocytes and endothelial cells consolidating the brain tissue parenchyma (7). Although, the anti-inflammatory effects of minocycline are known to some extent, the direct effects of neuroprotection have not been well investigated in neurodegenerative diseases.

Several studies have shown that the physiological neuroprotection mechanisms that occur after stroke are targeted through various signaling pathways. Several studies suggest that the mechanisms associated with either reducing the size of infarct or enabling neurorestoration, involve the following entities: (i) anti-high mobility group box-1 activity (8); (ii) NF-κB (9); (iii) mammalian target of rapamycin (mTOR) inhibitor (10, 11); (iv) stimulation of toll-like receptors (TLR2 and TLR4) prior to brain ischemia (12, 13), (v) c-Jun N-terminal kinase (JNK) inhibitor (14); (vi) p38 mitogen-activated protein kinase (p38 MAPK) inhibitor (15); (vii) MEK1 pathway (16); (viii) MAPP/MEK/ERK inhibitor (17); and (ix) Minocycline-induced reduction of LPS-stimulated p38 MAPK activation, and stimulation of the phosphoinositide 3-kinase (PI3K)/Akt pathway (18).

Currently, little is known about endogenous counter regulatory immune mechanisms that can induce neurorestoration. The glycogen synthase kinase-3β (AKT/GSK-3β) pathway has been recognized as a protective pathway against cerebral ischemic injury. In cerebral ischemia models, it has been shown that remote limb conditioning does indeed activate and upregulate the pro-survival AKT pathway (19) and long-term protection against cerebral ischemia is afforded by limb post-conditioning that is associated with AKT, MAPK, phosphatidylinositol 3-kinase (PI3K), and protein kinase C (PKC) signaling pathways (20). NF-κB transcription factor family members, such as p50, p65/RelA in the hippocampus, are regulated by metabotropic glutamate receptor signaling and c-Rel transcription factor is responsible for the formation and maintenance of long-term memory (21). Minocycline directly inhibits matrix metalloproteinase (MMP)-9 activation through NF-κB pathway (22). In silico modeling of anti-inflammatory response has been reported for endotoxins (LPS) and corticosteroids by activating TLRs in NF-κB (23).

Taken together, the modulation of cell survival and death signaling by hypoxic/ischemic preconditioning appears to be capable of targeting multiple levels of signaling cascades. Several inhibitors targeted the point of convergence through distinct and interacting signaling pathways (crosstalk mechanism) for inflammation by activating macrophages that lead to neuroprotection. Also, cerebral stimulation-based transcranial magnetic stimulation and direct current stimulation enhances brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) signaling (24, 25). In this study, we harness the convergent signaling pathways of pharmacotherapy (anti-inflammatory, immunomodulatory) and neurorehabilitation therapy (functional recovery) for efficient post-stroke neurorestoration by experimental and systems-level approach. We modeled using the systems biology approach of minocycline modulation of MMPs through NF-κB signaling pathway, a master regulator of inflammatory responses along with neurorehabilitation-based activation in BDNF and TrkB signaling.

More at link.

Disruption of brain-blood barrier might influence progression of Alzheimer’s

This probably means that this one cause of the neuronal cascade of death should be solved first.
Inflammatory action leaking through the blood brain barrier.
 But with NO strategy survivors are fucking screwed and our doctors and hospitals are laying down on the job. What the fuck is your doctor doing about MMP to alleviate this problem. ANYTHING AT ALL?
I've written 4 posts on MMP, one post on MMP-14, and 9 posts on MMP-9.
http://www.alphagalileo.org/ViewItem.aspx?ItemId=156807&CultureCode=en
VIB - Flanders Interuniversity Institute for Biotechnology
More and more data from preclinical and clinical studies strengthen the hypothesis that immune system-mediated actions contribute to and drive pathogenesis in Alzheimer’s disease. The team of Roosmarijn Vandenbroucke in the Claude Libert Group (VIB/UGent) combined their knowledge and expertise related to inflammation with the expertise in Alzheimer’s disease present in the Bart De Strooper Group (VIB/KU Leuven). This collaboration lead to the insights that Aβ indeed induces a strong inflammatory response, thereby destroying an important but often neglected brain barrier, called the blood-cerebrospinal fluid (CSF) barrier. Disruption of this blood-CSF barrier disturbs brain homeostasis and might negatively affect disease progression. Strikingly, these effects could be blocked in the presence of a matrix metalloproteinase (MMP) inhibitor.
Roosmarijn Vandenbroucke: “Although further research is needed, these data suggest that blocking MMP activity or upstream inflammatory signalling, might have therapeutic potential to treat Alzheimer’s disease. It is important we could demonstrate the role of the blood-cerebrospinal fluid barrier, because this would be an easier target to reach in comparison with the targets of current therapies.”
The publication of Vandenbroucke et al. was picked up by Alzforum.org who combined it together with another publication about the Blood-Brain Barrier:
Barriers Between Blood and CSF, Brain Yield to Aβ—Not a Bad Thing?
The barrier between the blood and central nervous system crumbles in Alzheimer’s disease, but researchers have known little about how this happens, or what it does to brain pathology. Two new papers shed some light on how Aβ damages the cells that protect the brain parenchyma and cerebrospinal fluid. The studies examine different systems and describe distinct mechanisms, but both add to the picture of what may happen in disease.
http://www.vib.be/en/news/Pages/Disruption-of-brain-blood-barrier-might-influence-progression-of-Alzheimer%E2%80%99s.aspx

Unbalanced metalloproteinase-9 and tissue inhibitors of metalloproteinases ratios predict hemorrhagic transformation of lesion in ischemic stroke patients treated with thrombolysis: results from the MAGIC study

Way out of my league, so you'll have to contact a genius somewhere to decipher this.
http://journal.frontiersin.org/article/10.3389/fneur.2015.00121/full?

Benedetta Piccardi¹*, Vanessa Palumbo², Mascia Nesi², Patrizia Nencini², Anna Maria Gori³, Betti Giusti³, Giovanni Pracucci¹, Paolina Tonelli¹, Eleonora Innocenti¹, Alice Sereni³, Elena Sticchi³, Danilo Toni⁴, Paolo Bovi⁵, Mario Guidotti⁶, Maria Rosaria Tola⁷, Domenico Consoli⁸, Giuseppe Micieli⁹, Rossana Tassi¹⁰, Giovanni Orlandi¹¹, Francesco Perini¹², Norina Marcello¹³, Antonia Nucera¹⁴, Francesca Massaro¹⁵, Maria Luisa DeLodovici¹⁶, Giorgio Bono¹⁶, Maria Sessa¹⁷, Rosanna Abbate³ and Domenico Inzitari^1,18, On behalf of the MAGIC Study Group

• ¹Neuroscience Section, Department of Neurofarba, University of Florence, Florence, Italy
• ²Stroke Unit, Department of Neurology, Careggi University Hospital, Florence, Italy
• ³Department of Experimental and Clinical Medicine, Atherothrombotic Diseases Center, AOU Careggi, University of Florence, Florence, Italy
• ⁴Emergency Department Stroke Unit, Department of Neurological Sciences, Sapienza University of Rome, Rome, Italy
• ⁵SSO Stroke Unit, U.O. Neurologia d.O., DAI di Neuroscienze, Azienda Ospedaliera Integrata, Verona, Italy
• ⁶Neurology Unit, Valduce General Hospital, Como, Italy
• ⁷U.O. Neurologia, DAI Neuroscienze-Riabilitazione, Azienda Ospedaliera-Universitaria S. Anna, Ferrara, Italy
• ⁸U.O. Neurologia, G. Jazzolino Hospital, Vibo Valentia, Italy
• ⁹Istituto Neurologico Nazionale C. Mondino, Pavia, Italy
• ¹⁰U.O.C. Stroke Unit, Dipartimento di Scienze Neurologiche e Neurosensoriali, Azienda Ospedaliera Universitaria Senese, Siena, Italy
• ¹¹Department of Neurosciences, Neurological Clinic, University of Pisa, Pisa, Italy
• ¹²UOC di Neurologia e “Stroke Unit”, Ospedale San Bortolo, Vicenza, Italy
• ¹³Neurology Unit, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy
• ¹⁴Department of Clinical Neurological Sciences, London Health Sciences Centre, Western University, London, ON, Canada
• ¹⁵Neurology Unit, Misericordia e Dolce Hospital, Prato, Italy
• ¹⁶Stroke Unit, Department of Neurology, Ospedale di Circolo e Fondazione Macchi, Varese, Italy
• ¹⁷Department of Neurology, Istituti Ospitalieri, Cremona, Italy
• ¹⁸Institute of Neuroscience, Italian National Research Council, Florence, Italy

Background: Experimentally, metalloproteinases (MMPs) play a detrimental role related to the severity of ischemic brain lesions. Both MMPs activity and function in tissues reflect the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs). We aimed to evaluate the role of MMPs/TIMPs balance in the setting of rtPA-treated stroke patients.

Methods: Blood was taken before and 24-h after rtPA from 327 patients (mean age 68 years, median NIHSS 11) with acute ischemic stroke. Delta median values of each MMP/TIMP ratio [(post rtPA MMP/TIMP-baseline MMP/TIMP)/(baseline MMP/TIMP)] were analyzed related to symptomatic intracranial hemorrhage (sICH) according to NINDS criteria, relevant hemorrhagic transformation (HT) defined as confluent petechiae within the infarcted area or any parenchymal hemorrhage, stroke subtypes (according to Oxfordshire Community Stroke Project) and 3-month death. The net effect of each MMP/TIMP ratio was estimated by a logistic regression model including major clinical determinants of outcomes

Results: Adjusting for major clinical determinants, only increase in MMP9/TIMP1 and MMP9/TIMP2 ratios remained significantly associated with sICH (odds ratio [95% confidence interval], 1.67 [1.17–2.38], p = 0.005; 1.74 [1.21–2.49], p = 0.003, respectively). Only relative increase in MMP9/TIMP1 ratio proved significantly associated with relevant HT (odds ratio [95% confidence interval], 1.74 [1.17–2.57], p = 0.006) with a trend toward significance for MMP9/TIMP2 ratio (p = 0.007).

Discussion: Our data add substantial clinical evidence about the role of MMPs/TIMPs balance in rtPA-treated stroke patients. These results may serve to generate hypotheses on MMPs inhibitors to be administered together with rtPA in order to counteract its deleterious effect.

Introduction

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are involved in extracellular matrix (ECM) degradation (1). The turnover of ECM is regulated by the balance between MMPs and a group of endogenous proteins called tissue inhibitor of metalloproteinases (TIMPs) (2). Active MMPs and some MMP proenzymes form 1:1 complexes with TIMPs and the unbalance between these two families of molecules appears implicated in a variety of diseases (3). A list of MMPs and TIMPs with their putative role in acute ischemic stroke is shown in Table S1 in Supplementary Material.

After cerebral ischemia, the general neuronal response to excitotoxic injury determines the release of pro-inflammatory cytokines that stimulate the local production of MMPs and TIMPs (4). In experimental models of brain ischemia, MMPs and MMP/TIMP unbalance play a detrimental role related to blood–brain barrier (BBB) disruption leading to hemorrhagic transformation and edema of an ischemic brain lesion (5). Circulating levels of MMP9 have been proved associated with poor outcomes in stroke patients treated with tissue plasminogen activator (rtPA) (6, 7). Furthermore, recent studies suggest that rtPA adverse effects may be mediated through MMPs upregulation and activation (2). No clinical study has hitherto considered selectively the effect of the balance between MMPs and their physiological inhibitor related to stroke outcomes after thrombolysis. Theoretical effects of rtPA on MMP/TIMP unbalance have been shown in Figure 1.

FIGURE 1

Figure 1. Impact of tissue plasminogen activator on MMP/TIMP unbalance at the neurovascular unit level. After acute ischemic stroke, rtPA may cross blood–brain barrier (BBB), enter the brain parenchyma, and thereby damage neurovascular unit components by promoting metalloproteinase (MMPs) production and activation. Indeed, unbalance between MMPs and their natural inhibitors (tissue inhibitors of metalloproteinases, TIMPs) may exacerbate BBB disruption leading to hemorrhagic transformation and edema of an ischemic brain lesion.

The aim of this study was to evaluate the effect of MMPs/TIMPs ratio on outcomes of ischemic stroke in the same cohort of the biological markers associated with acute ischemic stroke (MAGIC) study. Because MMP inhibition is considered a possible therapeutic target for stroke patients (8), a clearer understanding of MMP/TIMP interplay, compared with the effect of MMPs only, would have important implications for acute stroke therapies.

More at link.

Sequential Therapy with Minocycline and Candesartan Improves Long-Term Recovery After Experimental Stroke

Is this enough to start up human clinical trials? Ask your doctor and if your doctor doesn't do clinical trials you need to call the hospital president and ask why the stroke department head isn't solving stroke problems by doing clinical research.
http://link.springer.com/article/10.1007/s12975-015-0408-8

Sahar Soliman,

Tauheed Ishrat,

Abdelrahman Y. Fouda,

Ami Patel,

Bindu Pillai,

Susan C. Fagan

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Abstract

Minocycline and candesartan have both shown promise as candidate therapeutics in ischemic stroke, with multiple, and somewhat contrasting, molecular mechanisms. Minocycline is an anti-inflammatory, antioxidant, and anti-apoptotic agent and a known inhibitor of matrix metalloproteinases (MMPs). Yet, minocycline exerts antiangiogenic effects both in vivo and in vitro. Candesartan promotes angiogenesis and activates MMPs. Aligning these therapies with the dynamic processes of injury and repair after ischemia is likely to improve success of treatment. In this study, we hypothesize that opposing actions of minocycline and candesartan on angiogenesis, when administered simultaneously, will reduce the benefit of candesartan treatment. Therefore, we propose a sequential combination treatment regimen to yield a better outcome and preserve the proangiogenic potential of candesartan. In vitro angiogenesis was assessed using human brain endothelial cells. In vivo, Wistar rats subjected to 90-min middle cerebral artery occlusion (MCAO) were randomized into four groups: saline, candesartan, minocycline, and sequential combination of minocycline and candesartan. Neurobehavioral tests were performed 1, 3, 7, and 14 days after stroke. Brain tissue was collected on day 14 for assessment of infarct size and vascular density. Minocycline, when added simultaneously, decreased the proangiogenic effect of candesartan treatment in vitro. Sequential treatment, however, preserved the proangiogenic potential of candesartan both in vivo and in vitro, improved neurobehavioral outcome, and reduced infarct size. Sequential combination therapy with minocycline and candesartan improves long-term recovery and maintains candesartan’s proangiogenic potential.

Perth scientists embark on stroke therapy approach

The minocycline approach was researched/published in October 2009 so 4 years to maybe get it to a stroke protocol. Proving once again that the existing stroke associations are worthless.
http://www.sciencewa.net.au/topics/health-a-medicine/item/2324-perth-scientists-embark-on-stroke-therapy-approach.html
ROUTINE thrombolytic stroke therapy could be made safer through a new treatment strategy utilising the antibiotic minocycline, according to a stroke physician speaking at the Symposium of Western Australian Neuroscience.
The talk by Associate Professor David Blacker from Sir Charles Gardiner Hospital was part of the annual forum that aims to connect scientists and clinicians to people with neurological conditions and the wider community.
Currently, Prof Blacker along with neurologists from Royal Perth, Fremantle and Swan District Hospitals is investigating the efficacy and safety of combining two types of drug; minocycline and a clot-busting drug called tPA, to reduce complications with stroke therapy.
Prof Blacker says about 80 to 85 per cent of all strokes is ischemic.
“Ischemic strokes occur when blood vessels supplying blood to the brain are blocked by blood clots,” he says.
Following an ischemic stroke, the expression of a group of enzymes called matrix metalloproteinases (MMPs) is upregulated, which can disrupt the blood brain barrier, leading to haemorrhagic transformation.
“The most effective therapy for treating ischemic stroke involves the use of a clot-busting drug known as tissue plasminogen activator (tPA), which chemically dissolve blood clots,” he says.
According to Prof Blacker, tPA administration can be complicated by hemorrhagic transformation—the conversion of ischemic stroke into a haemorrhagic one (with a mixture of clotting and bleeding).
“This occurs in six to seven per cent of patients treated with tPA and has a mortality rate of up to 50 per cent.”
One way in which tPA related intracerebral haemorrhage could be reduced is through the use of minocycline.
Prof Blacker says minocycline is an inexpensive drug and can be used in patients with ischemic and haemorrhagic stroke.
“It also works by inhibiting brain MMPs activated by ischemia.”
Animal studies combining minocycline with tPA in rodent models of ischemic stroke have demonstrated significant reductions in MMPs and shown almost a 50 per cent reduction in rates of haemorrhagic transformation.
Funded by the Neurotrauma Research Program, the randomised pilot study, The West Australian Intravenous Minocycline and Thrombolysis Stroke Study will administer intravenous minocycline in patients with ischemic stroke treated with tPA, compared with no minocycline for patients treated with tPA.
“We have recruited 20 patients so far. Once we get our total number of patients up to 40 to 50, we may be able to conduct an interim analysis to gain a better understanding of the efficacy of the treatment.”
He says the study may be completed in early 2014.
The researchers hope to apply for more funding to conduct a phase-three trial.
Notes:
The Western Australian Symposium of Neuroscience was held at UWA on 23 July 2013.
It featured talks by eminent clinicians and neurologists as well as postgraduate student presentations.

Double-Agent MMP-9: Timing is Everything in Stroke Treatment

Plusses and minuses to everything.
http://www.ninds.nih.gov/news_and_events/news_articles/News_article_stroke_MMP.htm

For release: Thursday, August 03, 2006

In a surprise twist, researchers have learned that a type of enzyme that contributes to brain damage immediately after a stroke also plays a role in brain remodeling and movement of neurons days after stroke. Understanding the secondary role for this enzyme in healing stroke damage may lead to new treatments for stroke and offer a longer window of time for treatment.

Previous studies have shown that enzymes called matrix metalloproteinases (MMPs) contribute to stroke damage by chewing up and degrading the supporting material between the cells, called the cellular matrix. This can result in bleeding or cell death. Now, Eng Lo, Ph.D., and colleagues from the departments of radiology and neurology at Massachusetts General Hospital and the Harvard Medical School show that, days after a stroke, one of the MMPs, called MMP-9, moves into the stroke-affected area and helps repair damaged tissue. This new finding suggests that MMP-9 may be a double agent, meaning the same enzyme may cause good or bad results in the brain.

The study results were reported in The Journal of Neuroscience* and Nature Medicine.** Both studies were funded in part by the National Institute of Neurological Disorders and Stroke (NINDS).

MMP-9 is an enzyme which naturally exists in the brain. Currently tPA (tissue Plasminogen Activator), the only FDA-approved treatment for stroke, must be used within 3 hours of the onset of symptoms. While tPA helps to dissolve clots in blood vessels that cause strokes, it also increases levels of MMP-9, which can cause bleeding complications. MMP inhibitors seem to supplement the positive effects of tPA, and this has prompted researchers to propose that these drugs would be good candidates for stroke treatment. However, Dr. Lo’s research shows that inhibition of MMPs during the later time period after stroke actually hinders brain repair and may paradoxically increase the risk of bleeding in the brain.

“We need to think about the role of MMP-9 in stroke and its treatments as having two phases – an acute phase, which is damage producing, and a later phase, which helps with repair,” says Dr. Lo. “Treatments that affect MMP-9 will have different consequences depending on when they are given.”

“Early on in the developing brain, MMPs have a role to play in structuring and modeling. We have assumed that this beneficial role didn’t reoccur in the mature brain. However, we now know that the brain’s plasticity allows this initial remodeling to happen again,” says Dr. Lo.

Both studies used rodent models of stroke to examine the role of MMP-9 after brain injury. After stroke, neuroblasts (cells from which nerve tissue is formed) swerve away from their designated path and move towards damaged areas. This cellular migration requires help from special enzymes. The Journal of Neuroscience study shows that the migration of these cells through the tangle of damaged brain tissue uses MMPs. Researchers injected markers into the mouse brain to monitor the movement of the cells and examined their final location 14 days after the stroke. MMP-9 co-localized with these markers of neuroblast migration, and inhibiting MMP stopped the movement of these neurons to the damaged site. This is the first study to show that MMPs are required for neuroblast migration as the brain attempts to heal itself.

In the Nature Medicine study, Dr. Lo and his colleagues examined the action of MMPs with respect to timing after stroke damage. In rats, an MMP inhibitor was administered at different times after an induced stroke. When the injection was given immediately following the stroke, rats showed smaller areas of brain damage. Injections given at 3 days had no effect, while blocking MMPs at 7 days or 14 days led to more extensive brain damage in the treated rats. These findings highlight the time-dependent nature of MMP activity. Delayed inhibition of MMPs after a stroke seems to have negative effects, while early inhibition of MMPs may help protect the brain.

The scientists also examined the role MMPs play in remodeling within the brains of rats following stroke. Researchers located the enzymes in the damaged areas of the brain at 1 and 3 days after the stroke. However, 7 to 14 days after the stroke, high levels of MMPs were found instead in the region surrounding the initial damage, called the peri-infarct cortex. The peri-infarct cortex is the location where newly born immature neurons migrate and where axons sprout new connections after a stroke. The reorganization in the peri-infarct area is correlated with functional recovery after stroke. The increased presence of MMPs in this area suggests that it has a beneficial role in remodeling after brain injury.

“We need to think carefully about the use of MMP inhibitors after stroke and about their possible effects. Our current research shows that the brain is actively trying to heal itself after stroke,” says Dr. Lo. “This dynamic state of remodeling in the brain signals us to not give up hope after the initial stroke event and to recognize that the therapeutic window may be longer than we assumed.”

Previous studies have shown that MMPs contribute to blood vessel growth, as well as proliferation, differentiation and movement of cells. These diverse and important functions may explain the paradoxical positive and negative effects of MMPs. Future studies in Dr. Lo’s lab will examine the effects of low-dose and slow-release treatments with MMP-9 and MMP inhibitors. Dr. Lo hypothesizes that to achieve the biggest impact on stroke therapies, scientists must take into account the timing and specific brain area placement of MMP activity.

“It is a powerful lesson to learn that the same molecule can do very different things. Learning how to manipulate the system will be the key to developing improved treatments,” say Dr. Lo. “Combination therapy using tPA and short-term inhibitor MMPs would be invaluable for targeting acute treatment, while some way of modulating MMPs or controlling neurovascular proteolysis days later may provide a new approach for post-stroke therapy and could extend the narrow treatment time that we currently race against.”

The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.