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&
- 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.
Mohammed Aftab Alam
V. P. Subramanyam Rallabandi
Prasun K. Roy