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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open access
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. 1During
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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