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.

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