Astrocyte

POST STROKE RESTORATIVE THERAPIES: DRUGS, DEVICES AND ROBOTICS
Year
: 2018  |  Volume : 5  |  Issue : 1  |  Page : 39--42

Post stroke restorative therapies: Drugs, devices and robotics


MV Padma Srivastava, Ashu Bhasin 
 Department of Neurology, All India Institute of Medical Sciences, New Delhi, India

Correspondence Address:
M V Padma Srivastava
Department of Neurology, All India Institute of Medical Sciences, New Delhi
India

Abstract

Restorative therapies in neurology aim to improve outcome and function by promoting plasticity within a therapeutic time window between days to weeks to years. In this article, the mechanisms by which cell-based, pharmacological and robotic treatments stimulate endogenous brain remodeling after stroke, particularly neurogenesis, axonal plasticity, and white-matter integrity, are described with a brief outline of the potential of neuroimaging (functional magnetic resonance imaging) techniques. Stem cells aid stroke recovery through mechanisms depending on the type of cells used. Transplanted embryonic stem cells, induced pluripotent cells, and neural stem cells can replace the missing brain cells in the infarcted area, whereas adult stem cells, such as multipotent stromal cells and mononuclear cells, provide trophic support to enhance self-repair systems such as endogenous neurogenesis. Noninvasive brain stimulation provides a valuable tool for interventional neurophysiology by modulating brain activity in a specific distributed, corticosubcortical network. Elucidating the underlying mechanisms of cell-based, pharmacological and rehabilitative therapies is of primary interest and crucial for translation of treatments to clinical use. This will provide an impetus for the development of superior, advanced, and cost-effective neurorestorative interventions that will enhance stroke recovery.



How to cite this article:
Padma Srivastava M V, Bhasin A. Post stroke restorative therapies: Drugs, devices and robotics.Astrocyte 2018;5:39-42


How to cite this URL:
Padma Srivastava M V, Bhasin A. Post stroke restorative therapies: Drugs, devices and robotics. Astrocyte [serial online] 2018 [cited 2019 Jul 16 ];5:39-42
Available from: http://www.astrocyte.in/text.asp?2018/5/1/39/250919


Full Text

 Introduction



Restorative therapies aim to improve outcome and function by promoting plasticity within a therapeutic time window between days to weeks to years. The armamentarium includes growth factors, cell-based therapies, drugs, and devices. Pharmacological treatment includes drugs that increase cyclic guanosine monophosphate (cGMP; e.g. phosphodiesterase 5 inhibitors, such as sildenafil and tadalafil), statins, erythropoietin, granulocyte-colony stimulating factor, and minocycline.[1],[2],[3],[4]

Cell-based interventions: Stem cells

Stem cells can be defined as clonogenic cells that have the capacity to self-renew and differentiate into multiple cell lineages. They are divided according to the body's development process and their ability to form other cells.[5],[6],[7],[8],[9],[10] Their presumed participation in repair and regeneration raised high expectations to cure diseases that have thus far proven resistant to conventional therapy such as stroke.

Human umbilical cord blood cells

These cells are derived from umbilical cord blood with a potential of differentiation into neural lineages. When exposed to nerve growth factor and retinoic acid, the derived umbilical cord blood cells produce progeny that shows positivity for neural and glial cells' markers.[11]

Immortalized cell lines

These cell lines are derived by infecting neuroepithelial precursor cells from predefined central nervous system (CNS) regions before terminal mitosis, with a retrovirus encoding an immortalizing oncogene.[12]

Fetal neural stem cells

These cells maintain a normal karyotype for a significant number of passages in culture and can produce a large number of neurons and astrocytes and are harvested from the postmortem human fetal brain.[13]

Adult neural stem cells

Neural stem cells are defined as undifferentiated cells that are able to self-renew and generate three major cell types of CNS: neurons, astrocytes, and oligodendrocytes, signifying their pluripotent nature.[5],[6],[13]

Bone marrow–derived cells

These have hematopoietic and nonhematopoietic components, the former being abundant in bone marrow.[14] Mobilized peripheral blood is also a clinical source of heme cells, containing a mixture of hematopoietic stem and progenitor cells enriched with CD34.[15] These cells have the potential to regenerate the brain tissue by release of neurotrophic growth hormones. The other component of bone marrow contains mesenchymal stem cells or multipotent stromal cells described as colony-forming units that adhere to cell culture surfaces and can be differentiated into osteoblasts, adipocytes, and chondrocytes.[16],[17],[18]

Induced pluripotent cells

These cells are similar to human embryonic stem cells in morphology, proliferation, surface antigens, gene expression, epigenetic status of pluripotent cell-specific genes, and telomerase activity.[19]

 Clinical Trials of Stem Cell Research in Stroke



Among all types of cells, bone marrow–derived stem cells are used frequently in clinical trials with stroke. Multiple studies from AIIMS, New Delhi, report successful transplanted bone marrow–derived mononuclear and mesenchymal stem cells in chronic stroke.[20],[21],[22] The functional benefits after neural transplantation are likely to be mediated by one of a host of hypothesized mechanisms.[23],[24]

Another observational controlled study evaluated the feasibility and efficacy of autologous mononuclear stem cells' infusion intravenously in patients with chronic ischemic stroke using clinical scores and functional imaging (functional magnetic resonance imaging and diffusion tensor imaging). Of 24 patients recruited, 12 received a mean of 54.6 million Mononuclear stem cells (MNC) cells. On follow-up of 24 weeks, only modified Barthel index (mBI) showed statistically significant improvement (P < 0.05) in the stem cells' arm. There was an increased number of cluster activation of Brodmann areas BA4 and 6, after stem-cell infusion. Similar results were observed in a parallel study using culture expanded autologous mesenchymal stem cells.[20],[21],[25]

 Role of Noninvasive Brain Stimulation



Noninvasive brain stimulation (NIBS) provides a valuable tool for interventional neurophysiology by modulating brain activity in a specific distributed, corticosubcortical network.[26],[27],[28],[29],[30],[31] The two most commonly used techniques for NIBS are transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). TMS is a neurostimulation and neuromodulation application, whereas tDCS is a purely neuromodulatory intervention.[32],[33],[34],[35]

Hsu et al. conducted a meta-analysis on 18 studies involving 392 patients on efficacy of TMS after stroke. A significant effect size of 0.55 was found for motor outcome [95% confidence interval (CI), 0.37–0.72) with subgroup analyses demonstrating more prominent effects on subcortical stroke (mean effect size ~0.73; 95% CI, 0.44–1.02).[30] Recent data suggest that intermittent theta-burst stimulation over the affected hemisphere might be a useful intervention.[36],[37]

In tDCS, although the currents applied do not usually elicit action potentials, they modify the transmembrane neuronal potential and thus influence the level of excitability modulating the firing rate of individual neurons.[38],[39]

 Role of Mirror Therapy/virtual Reality



A pilot study confirmed the positive effects of mirror therapy on facilitation in upper limb hemiparesis after stroke.[40] In a systematic review, 14 studies were included with 9–121 participants. It was found that mirror therapy had a significant effect on motor function (Standard mean deviation (SMD) 0.61; 95% CI, ~0.22 to1; P = 0.002; I2 = 75%).[41] A study from AIIMS, New Delhi, used mirror therapy in chronic stroke patients with the help of a web cam that captured the normal hand which was seen as affected on the laptop screen. Bilateral hand training was administered to patients and it was observed that Mirror therapy (MT) improved hand function in FM and mBI scores along with an increased in laterality index in ipsilesional BA 4 and 6.[42]

 Role of Cimt and Electrical Stimulation



Constraint-induced movement therapy (CIMT) has been investigated in 51 randomized controlled trials (RCTs) including 1784 patients with adult stroke; only 15 trials included patients within the first 3 months after stroke. From systematic review,[43],[44],[45] it is evident that original and modified versions of CIMT have a robust, clinically meaningful impact on patient's outcomes for arm-hand activities, self-reported hand use in daily life, and basic activities of daily living, making it one of the most effective interventions for the paretic limb after stroke. Neuromuscular electrical stimulation and functional electrical stimulation induce depolarization of peripheral neurons and subsequently elicit muscle contractions.[46],[47]

 Robotic Technology in Stroke



The introduction of robotic systems into clinical practice is useful in promoting a cost-effective use of human resources and standardization of rehabilitation treatments.[48],[49],[50],[51],[52]

 Pharmacological Agents



Nitric oxide

Nitric oxide (NO) is an “endothelial-derived relaxing factor” which is involved in maintaining endothelial cell integrity, and participating in hemodynamic homeostasis.[53] The increased expression of neuronal NO synthase within the subvenricular zone during embryogenesis suggests an important role for the NO pathway in neurogenesis, increasing cGMP levels, and aid in recovery.[54]

GABA: Gamma amino butyric acid

GABA may help in recovery after stroke involving remapping of the neuronal circuitry in the regions adjacent to the site of injury or the peri-infarct zone.[55],[56]

Selective serotonin reuptake inhibitors

Animal studies suggest that selective serotonin reuptake inhibitors (SSRIs) may be involved in neurogenesis and activation of cortical motor areas modulating neuronal plasticity.[57] A meta-analysis of RCTs onstroke patients treated with SSRI compared with usual care or sham found that these drugs are associated with an improvement in functionality, neurological impairment, disability, and depression.[58],[59],[60]

Minocycline

Studies have shown that minocycline has notable beneficial effects in animal models of global and transient focal cerebral ischemia.[61],[62] In a randomized single-blinded study, we studied the effects of oral minocycline (200 mg/day for 5 days) after stroke versus placebo. Of 50 patients included in the trial, patients who received minocycline had better recovery in stroke outcome as noted on National institute of health stroke scale (NIHSS), mBI and modified rankin score (mRS).[63]

 Conclusion



Neurorestoration is a concept that has been proven emphatically in several experimental models and clinical studies of stroke. Elucidating the underlying mechanisms of cell-based, pharmacological and rehabilitative therapies is crucial for translation of treatments to clinical use. The knowledge must provide an impetus for the development of superior, advanced, and cost-effective neurorestorative interventions that will enhance stroke recovery.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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