Can kinase trafficking to mitochondria unlock new targets in ischemic stroke?

 Ask your competent? doctor to translate this word salad to layperson terms. Will something from here get survivors to 100% recovery?

Can kinase trafficking to mitochondria unlock new targets in ischemic stroke?

Stroke is a major cause of death and permanent disability, which is described by abrupt loss of neuronal energy, oxidative injury, inflammation, and apoptosis, primarily mediated by mitochondrial dysfunction. Mitochondria are key regulators of stress responses, apoptosis, redox homeostasis, immune signaling and known as central signaling hubs, integrating pathways from multiple cellular compartments to maintain homeostasis. Among the major regulatory elements are protein kinase enzymes that modulate cell signaling by phosphorylating substrates. Several kinases, including members of the Akt, PKA, PKC, GSK-3β, PINK1, and MAPK families, dynamically translocate to mitochondria under physiological and pathological conditions. Once localized, they influence mitochondrial dynamics, bioenergetics, reactive oxygen species (ROS) production, and programmed cell death. Dysregulation of these functions has been implicated in impaired mitophagy, aberrant calcium signaling, and processes associated with the pathogenesis of various neurological disorders, particularly in those with acute brain injuries, such as acute ischemic stroke (AIS). Especially, mitochondrial kinase oxidative stress hallmarks of neuronal injury. In this review, we examine the role of mitochondrial-associated kinases in AIS, explore mechanisms of their translocation, downstream signaling effects, and their promise as druggable targets highlighting the importance of spatial dynamics of kinases and the need for precision therapies. Understanding these mechanisms may open new avenues for therapeutic intervention in neurological diseases with a focus on acute brain injury, by targeting mitochondrial signaling networks.

Role of Akt-independent mTORC1 and GSK3β signaling in sublethal NMDA-induced injury and the recovery of neuronal electrophysiology and survival

Followup needed since nothing here can be directly used to help your recovery.
https://www.ncbi.nlm.nih.gov/pubmed/28484273

Swiatkowski P^1,2, Nikolaeva I^1,2, Kumar G¹, Zucco A^1,3, Akum BF¹, Patel MV^1,3, D'Arcangelo G¹, Firestein BL⁴.

Author information

Abstract

Glutamate-induced excitotoxicity, mediated by overstimulation of N-methyl-D-aspartate (NMDA) receptors, is a mechanism that causes secondary damage to neurons. The early phase of injury causes loss of dendritic spines and changes to synaptic activity. The phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt/ mammalian target of rapamycin (PI3K/Akt/mTOR) pathway has been implicated in the modulation and regulation of synaptic strength, activity, maturation, and axonal regeneration. The present study focuses on the physiology and survival of neurons following manipulation of Akt and several downstream targets, such as GSK3β, FOXO1, and mTORC1, prior to NMDA-induced injury. Our analysis reveals that exposure to sublethal levels of NMDA does not alter phosphorylation of Akt, S6, and GSK3β at two and twenty four hours following injury. Electrophysiological recordings show that NMDA-induced injury causes a significant decrease in spontaneous excitatory postsynaptic currents at both two and twenty four hours, and this phenotype can be prevented by inhibiting mTORC1 or mTORC1, but not Akt. Additionally, inhibition of mTORC1 or GSK3β promotes neuronal survival following NMDA-induced injury. Thus, NMDA-induced excitotoxicity involves a mechanism that requires the permissive activity of mTORC1 and GSK3β, demonstrating the importance of these kinases in the neuronal response to injury.

PMID:

28484273

PMCID:

PMC5431483

DOI:

10.1038/s41598-017-01826-w

Free PMC Article

Protection after stroke: cellular effectors of neurovascular unit integrity

Now if we just had a great stroke association that would take this information and create translational stroke protocols to stop parts of the neuronal cascade of death. But we have crap for stroke associations and thus future survivors will continue to not have any useful stroke protocols in the first week.
http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00231/full?

Rafael Andres Posada-Duque¹, George E. Barreto² and Gloria Patricia Cardona-Gomez^1*

• ¹Cellular and Molecular Neurobiology Area, Group of Neuroscience of Antioquia, Faculty of Medicine, Sede de Investigación Universitaria (SIU), University of Antioquia UdeA, Medellín, Colombia
• ²Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia

Neurological disorders are prevalent worldwide. Cerebrovascular diseases (CVDs), which account for 55% of all neurological diseases, are the leading cause of permanent disability, cognitive and motor disorders and dementia. Stroke affects the function and structure of blood-brain barrier, the loss of cerebral blood flow regulation, oxidative stress, inflammation and the loss of neural connections. Currently, no gold standard treatments are available outside the acute therapeutic window to improve outcome in stroke patients. Some promising candidate targets have been identified for the improvement of long-term recovery after stroke, such as Rho GTPases, cell adhesion proteins, kinases, and phosphatases. Previous studies by our lab indicated that Rho GTPases (Rac and RhoA) are involved in both tissue damage and survival, as these proteins are essential for the morphology and movement of neurons, astrocytes and endothelial cells, thus playing a critical role in the balance between cell survival and death. Treatment with a pharmacological inhibitor of RhoA/ROCK blocks the activation of the neurodegeneration cascade. In addition, Rac and synaptic adhesion proteins (p120 catenin and N-catenin) play critical roles in protection against cerebral infarction and in recovery by supporting the neurovascular unit and cytoskeletal remodeling activity to maintain the integrity of the brain parenchyma. Interestingly, neuroprotective agents, such as atorvastatin, and CDK5 silencing after cerebral ischemia and in a glutamate-induced excitotoxicity model may act on the same cellular effectors to recover neurovascular unit integrity. Therefore, future efforts must focus on individually targeting the structural and functional roles of each effector of neurovascular unit and the interactions in neural and non-neural cells in the post-ischemic brain and address how to promote the recovery or prevent the loss of homeostasis in the short, medium and long term.

Introduction

Neurological disorders are highly prevalent around the globe. In 2008, neurodegenerative disorders were responsible for 1% of disabilities worldwide (W.H.O., 2003). Strokes account for 55% of all neurological diseases and are considered the leading cause of permanent physical and mental disability (OMS, 2013). The primary risk factors of stroke include hyperlipidemia, hypertension, diabetes mellitus, and harmful habits, such as smoking and excessive alcohol consumption. The high incidence of strokes is related to an increased number of dementia cases and other emotional and cognitive disorders, such as depression and memory loss (Ovbiagele and Nguyen-Huynh, 2011). Death, physical deterioration, and altered quality of life are consequences of the natural history of strokes among patients who survive an ischemic event (Sacco, 1997, 1998; Feigin et al., 2003; Silva et al., 2006). Interestingly, the coexistence of cerebral ischemia and neurodegenerative pathologies profoundly impacts the development of dementia, suggesting a reciprocal interaction between ischemia and neurodegeneration (Nagy et al., 1997; Snowdon et al., 1997). These observations, along with the results of epidemiological studies that have indicated that Alzheimer’s disease (AD) and cerebrovascular diseases share similar risk factors (Breteler, 2000), have shifted interest to vascular factors as fundamental contributors to the pathogenesis of neurodegenerative diseases (de la Torre and Mussivand, 1993; Kalaria, 2000; Iadecola and Gorelick, 2003). This hypothesis has been supported by the experimental findings that showed that amyloid-beta (Aβ) peptide, which is commonly detected in AD patients, exhibits strong cerebrovascular effects and that ischemia-induced responses to hypoxia are potent modulators of cerebral amyloidogenesis (Iadecola, 2004). Both Aβ peptide and vascular risk factors deteriorate the structure and function of the neurovascular unit (NVU, consisting of the endothelium, glia, neurons, pericytes, and the basal lamina) (Mirra and Gearing, 1997; Snowdon et al., 1997; Breteler, 2000; Kalaria, 2000; Iadecola and Gorelick, 2003; Iadecola, 2004).

The NVU acts as a guardian of cerebral homeostasis. Neurons, glia, the perivascular space, and the endothelium are closely interrelated to maintain the homeostasis of the brain microenvironment (Iadecola, 2010), regulate blood flow, modulate the exchange across the blood-brain barrier (BBB), contribute to immune vigilance and provide trophic support to the brain (Iadecola, 2010). Substantial evidence has shown that cerebrovascular dysfunction is implicated in not only cognitive impairment (such as that of cognitive origin) but also neurodegenerative diseases, such as AD (Chui et al., 1992; Alavi et al., 1998; Kalaria, 2000; Iadecola, 2004; Simpkins et al., 2005; Hachinski et al., 2006; Pendlebury et al., 2012). Ischemic stroke is exacerbated by several risk factors that affect the function and structure of blood vessels in the brain and cells associated with the NVU, reducing the ability of the brain parenchyma to repair due to the rupture of the BBB, the loss of brain blood flow regulation, oxidative stress, inflammation, and the loss of neuronal connections, ultimately increasing brain dysfunction (Deane et al., 2003; Ohab et al., 2006; Konsman et al., 2007; Weber et al., 2007; Bell et al., 2009; Wolburg et al., 2009). The study of stroke has focused on understanding the molecular and pathophysiological mechanisms of neuronal death, recovery and pharmacological intervention strategies, as well as clinical and epidemiological characteristics (Silva et al., 2006). In addition, several molecular targets associated with endothelial dysfunction and cardio-cerebrovascular risk, including CDK5, Rho GTPases, and cell adhesion proteins, are described below and presented in a hypothetical schematic in Figure 1 to explain and propose a potential neuroprotective approach for stroke.

Much more at link.