Changing stroke rehab and research worldwide now.Time is Brain! trillions and trillions of neurons that DIE each day because there are NO effective hyperacute therapies besides tPA(only 12% effective). I have 523 posts on hyperacute therapy, enough for researchers to spend decades proving them out. These are my personal ideas and blog on stroke rehabilitation and stroke research. Do not attempt any of these without checking with your medical provider. Unless you join me in agitating, when you need these therapies they won't be there.

What this blog is for:

My blog is not to help survivors recover, it is to have the 10 million yearly stroke survivors light fires underneath their doctors, stroke hospitals and stroke researchers to get stroke solved. 100% recovery. The stroke medical world is completely failing at that goal, they don't even have it as a goal. Shortly after getting out of the hospital and getting NO information on the process or protocols of stroke rehabilitation and recovery I started searching on the internet and found that no other survivor received useful information. This is an attempt to cover all stroke rehabilitation information that should be readily available to survivors so they can talk with informed knowledge to their medical staff. It lays out what needs to be done to get stroke survivors closer to 100% recovery. It's quite disgusting that this information is not available from every stroke association and doctors group.

Saturday, January 25, 2025

Role of astrocytes connexins - pannexins in acute brain injury

 

 Notice how long ago all this hemichannel research was published. Why is your stroke hospital president still president and the board of directors still there?  I would have all of them fired for cause. There is so much incompetence in stroke it's unbelievable these people still have jobs!  And the result of that incompetence falls on stroke survivors NOT RECOVERING!

Send me hate mail on this: oc1dean@gmail.com. I'll print your complete statement with your name and my response in my blog. Or are you afraid to engage with my stroke-addled mind? No excuses are allowed! You're medically trained; it should be simple to precisely refute all my points with NO EXCUSES!! And what is your definition of competence in stroke? Swearing at me is allowed, I'll return the favor. Don't even attempt to use the excuse that brain research is hard.

The early stuff here:

New approach to stroke treatment could minimize brain damage Mar 14, 2019 

The latest here:   

Role of astrocytes connexins - pannexins in acute brain injury

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https://doi.org/10.1016/j.neurot.2025.e00523
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Abstract

Acute brain injuries (ABIs) encompass a broad spectrum of primary injuries such as ischemia, hypoxia, trauma, and hemorrhage that converge into secondary injury where some mechanisms show common determinants. In this regard, astroglial connexin and pannexin channels have been shown to play an important role. These channels are transmembrane proteins sharing similar topology and form gateways between adjacent cells named gap junctions (GJs) and pores into unopposed membranes named hemichannels (HCs). In astrocytes, GJs and HCs enable intercellular communication(Sounds extremely important, your competent? doctor should have protocols to enable this' But s/he doesn't, which means you DON'T have a functioning stroke doctor, do you?) and have active participation in normal brain physiological processes, such as calcium waves, synapsis modulation, regional blood flow regulation, and homeostatic control of the extracellular environment, among others. However, after acute brain injury, astrocytes can change their phenotype and modify the activity of both channels and hemichannels, which can result in the amplification of danger signals, increased mediators of inflammation, and neuronal death, contributing to the expansion of brain damage and neurological deterioration. This is known as secondary brain damage. In this review, we discussed the main biological mechanism of secondary brain damage with a particular focus on astroglial connexin and pannexin participation during acute brain injuries.


Introduction

Acute brain injuries (ABIs) are a group of heterogeneous diseases that produce alterations in neuronal activity and physical integrity or function of one or more areas of the brain after birth. ABIs are characterized by an acute clinical presentation in the range of minutes to hours, and a worldwide distribution with high morbidity, mortality, and devastating sequelae [1]. ABIs include stroke, intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), and hypoxic encephalopathy (HE). Stroke, englobing ischemic, ICH, and SAH are the second and third leading causes of death and disability worldwide, respectively [2]. TBI is the primary cause of death and permanent brain damage in individuals younger than 45 years old [3]. The main causes of TBI are road injuries and falls at extreme ages (children and elderly). Therefore, an approximate sum of the casualties related to ABIs provides us with the group of diseases with the greatest epidemiological impact.
Regardless of etiology, ABIs are characterized by one or more primary damage zones at injury foci, which propagate damage signals to neighboring parenchyma by systemic and local mechanisms. After an ABI (hypoxic-ischemic, hemorrhagic, or traumatic) a complex cascade of damage progression takes place, becoming independent from the initial injury. This involves both systemic and local factors, which contribute to the expansion of the original injury. This subsequent phase is known as secondary brain injury (SBI) and occurs in all ABIs with varying degrees of severity. Among systemic factors, the presence of hypotension and hypoxia doubles the likelihood of a poor neurological outcome [4]. Other well-known systemic factors for SBI are hyper and hypocapnia, hyponatremia, anemia, hypoglycemia, and fever [[5], [6], [7], [8], [9]]. Local factors for SBI include cellular and tissue biological mechanisms that amplify the injury including ischemia, excitotoxicity, inflammation, apoptosis, oxidative stress, mitochondrial dysfunction, edema, and cortical spreading depression [10].
A prominent component of SBI is the astrocyte participation. Reactive or dysfunctional astrocytes are critical for the propagation of damage to unaffected brain tissue. Several studies have shown that the latter could be associated with the dysfunction of the astrocyte syncytium, the transmission of cell-to-cell damage signals by gap-junctions or by paracrine signaling through connexin (Cx) hemichannels (HCs) or pannexins channels (Panx) [[11], [12], [13]]. Indeed, the genetic reduction of Cx43, the main Cx-base channels in the astrocytes, has been shown to reduce astrocytic activation and neuronal cell death [[14], [15], [16]]. On the other hand, Panx1 channels, have been described to activate the inflammasome in astrocytes and neurons and form large pores in the cell membrane whose activation can worsen the brain injury [17,18]. Interestingly, some studies have shown for example that the inhibition of Panx1 with probenecid can protect the brain against oxygen-glucose deprivation injury in primary astrocytes, and early brain injury after subarachnoid hemorrhage [19,20].
In this review, we examine the local mechanisms involved in secondary brain injury, describing their significance, main features, roles for the pathophysiology of acute brain injury and with a special focus on how astrocytic Cx43 ​HCs and Panx1 channels contribute to the propagation of danger signals and subsequent neuronal damage after injury.

Astrocyte functions

Astrocytes are the most abundant fraction of glial cell types in the central nervous system (CNS) playing vital roles in maintaining CNS homeostasis. Their functions include providing structural support, contributing to the blood-brain barrier, regulating synaptic transmission, controlling local blood flow, and maintaining the extracellular fluid balance in the brain, such as fine regulation of [K+]e, [H+]e, glutamate, and water [[21], [22], [23]]. A main characteristic of astrocytes is their highly complex 3D morphology with many fine processes. These processes cover over 80 ​% of the astrocytic plasma membrane, and more than 56 ​% of neuronal synapses are connected to them [24]. Indeed, this physical proximity allows astrocytes to modulate synaptic activity, leading to the concept of tripartite synapses, which involve the pre-and postsynaptic neurons along with an astrocyte process [25].
Intercellular communication in the tripartite synapsis is key to their role in both maintaining homeostasis and contributing to injury. Astrocytes are highly interconnected through connexin-based channels, forming functional syncytia allowing the spatial buffering of K+, H+, and glutamate in the brain (Fig. 1) [26].
Fig. 1
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Fig. 1
During acute brain injuries, in the lesion core, neural cells die by necrosis and release damage-associated molecular patterns (DAMPs) including HMGB1, HSPs, S100B, ATP, and glutamate [35]. DAMPs can induce NF-κB signaling through pattern recognition receptors (eg. Toll-like receptors and RAGE) activating glial cells and changing their phenotype promoting the clearance of cellular debris by phagocytic cells [36]. This reactive astrogliosis is preceded by microglial activation and starts within hours after the lesion, and is characterized by changes in gene expression profile, morphology, functional dynamics, and inflammatory profile expression [37,38]. Under pathological conditions, reactive astrogliosis can lead to injury recovery, for example, by the formation of “glial scar” to isolate the injury from healthy tissue, the secretion of neurotrophic mediators, and repair of synapses and blood-brain barrier (BBB), but also to the exacerbation of the inflammation, promoting the infiltration of inflammatory cells through the damaged BBB and inducing the spread of neuronal death [39]. Astroglial reactivity is highly context-dependent and defines a broad spectrum of phenotypes ranging from homeostatic to pathologic [39,40]. For instance, after a TBI some reactive astrocytes proliferate to isolate damaged tissue while others more distant extend their processes toward the injury [41]. These cells upregulate the expression of the glial fibrillary acidic protein (GFAP) and reduce the expression of homeostatic proteins such as glutamate transporter (eg. GLT-1), glutamine synthetase (GS), inwardly rectifying potassium channel Kir4.1 and Cx43 based gap junction channels resulting in the uncoupling of the syncytia, likely to avoid the bystander effect from injured cells [16,42,43]. Interestingly, several studies also have shown that ABIs induce an increase in the expression and activity of the Cx43 HC and pannexins channel along with an increase in inflammatory mediators. For example, in several animal models of TBI, spinal cord injury (SCI), myelin injury, and hypoxic ischemia (HI), increased expression and activity of Cx43 HC and Panx1 was observed, along with increased astrogliosis, inflammatory cell infiltration, high extracellular levels of glutamate, ATP, HMGB1, proinflammatory cytokines such as IL-1β, IL-6, and TNF-α, increased neuronal autophagy (LC3-II), and apoptosis through caspase-3 activation. These effects were decreased when Cx43 or Panx1 were blocked using genetic or pharmacologic approaches [16,17,[44], [45], [46], [47], [48], [49], [50], [51]], suggesting that astrocytic Cx43 HC and Panx1 channel could be potential targets for therapeutic interventions in ABIs.

Connexins and pannexins proteins

Connexins (Cxs) are assembled transmembrane proteins that allow intercellular communication in two ways: (1) connecting cytoplasm of adjacent cells through gap junction channels (GJCs) made by the docking of two connexons or HCs located at opposed membranes between cells and (2) paracrine signaling, through HCs located at unopposed domains of cell surfaces. Each HC is an array of six Cxs surrounding a central pore called connexon. There are 21 Cxs in the human genome named according to their molecular weight [52], and 11 are known to be expressed in CNS [53]. GJCs allow direct cell-to-cell exchange of small molecules, ions, and second messenger as Ca2+ and inositol trisphosphate (IP3). GJCs coupling enables a functional syncytium, allowing for spatial buffering of small molecules in the astrocytic network. HCs permit the exchange of molecules and ions between the cytoplasm and the external medium, supporting autocrine and paracrine actions [54]. Interestingly, Cx43 ​HCs and Cx43 GJCs are regulated oppositely by intracellular Ca2+ (Ca2+i) and by pro-inflammatory cytokines impairing the syncytium properties of astrocytes [55].
Cx43 HC has several regulatory and phosphorylation sites for MAPK and PKC in the C-terminal tail. While MAPK activity has been described in the fully activated state of Cx43 HC, PKC regulates its activity by increasing the perm-selectivity of Cx43 (the ability to discriminate between cations and anions) [[27], [28], [29], [30]] (Fig. 1, A). Interestingly, Chen et al. found in TBI patients who underwent brain surgery, that Cx43 protein levels were negatively associated with the extent of disease severity. However, Cx43 phosphorylation status was strongly associated with extremely severe cases that also had high kinase activities for MAPK and PKC [56]. Supporting the role of Cx43 phosphorylation in the pathology, Freitas-Andrade et al., found that knocking out phosphorylation sites for MAPK sites in Cx43 (Cx43 S255/262/279/282A), decreased the infarct volume and improved behavioral performance in a mouse model of stroke induced by permanent middle cerebral artery occlusion [29]. Contrary to what Chen et al. found in their study on TBI patients, some experimental animal models for ABIs, have shown a transient induction in the levels of total Cx43 and p-Cx43 after brain injury induction, suggesting that Cx43 HC activity has a key role in the severity of ABI (Table 1). The differences can be explained by intracellular redistribution of the protein and its degradation over time.

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