Systems Biology of Immunomodulation for Post-stroke Neuroplasticity: Multimodal Implications of Pharmacotherapy and Neurorehabilitation

It would seem that this should have been broken into multiple trials. Putting anti-inflammation drugs, tDCS, and rTMS into the same trial  is a recipe for not knowing which intervention did what.  A good mentor would have known that and changed the trial appropriately.
http://journal.frontiersin.org/article/10.3389/fneur.2016.00094/abstract

Mohammed A. Alam¹, V.P. S. Rallabandi¹ and Prasun K. Roy^1*

• ¹National Brain Research Centre, 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 antiinflammatory 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 NF-κB (nuclear factor kappa beta) signaling and neurorehabilitation therapy using tDCS and rTMS which 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, Trk-B and Calmodulin kinase (CaMK) signaling. Utilizing systems biology approach, we show 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 (NMDA) 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.

Keywords: Stroke, Neuroprotection, Rehabilitation, Minocycline, direct current stimulation, Transcranial magnetic stimulation.
Citation: Alam MA, Rallabandi VS and Roy PK (2016). Systems Biology of Immunomodulation for Post-stroke Neuroplasticity: Multimodal Implications of Pharmacotherapy and Neurorehabilitation. Front. Neurol. 7:94. doi: 10.3389/fneur.2016.00094

Received: 22 Jan 2016; Accepted: 07 Jun 2016.

Edited by:
Anirban Dutta, Leibniz-Institut für Arbeitsforschung an der TU Dortmund, Germany

Reviewed by:
Raju S. Bapi, University of Hyderabad, India
Mamta Naidu, GRI/ CCSB-Tufts Sch Med, USA  

Copyright: © 2016 Alam, Rallabandi and Roy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Prasun K. Roy, National Brain Research Centre, NH-8, Nainwal Road, Manesar, Grgaon, 122051, Haryana, India, pkroy@nbrc.ac.in