Abstract
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. 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. 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. 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.
Highlights
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]
The anti-inflammatory effects of minocycline are known to some extent, the direct effects of neuroprotection have not been well investigated in neurodegenerative diseases
Activation input was in the form of a constant single impulse or step function, while for the transcranial direct current stimulation and repetitive transcranial magnetic stimulation inputs, we used repeated series of electrical or magnetic pulses involved in cerebral stimulation
Summary
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]. 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]. The anti-inflammatory effects of minocycline are known to some extent, the direct effects of neuroprotection have not been well investigated in neurodegenerative diseases
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