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Recent Investigations on Neurotransmitters’ Role in Acute White Matter Injury of Perinatal Glia and Pharmacotherapies—Glia Dynamics in Stem Cell Therapy

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Abstract

Periventricular leukomalacia (PVL) and cerebral palsy are two neurological disease conditions developed from the premyelinated white matter ischemic injury (WMI). The significant pathophysiology of these diseases is accompanied by the cognitive deficits due to the loss of function of glial cells and axons. White matter makes up 50% of the brain volume consisting of myelinated and non-myelinated axons, glia, blood vessels, optic nerves, and corpus callosum. Studies over the years have delineated the susceptibility of white matter towards ischemic injury especially during pregnancy (prenatal, perinatal) or immediately after child birth (postnatal). Impairment in membrane depolarization of neurons and glial cells by ischemia-invoked excitotoxicity is mediated through the overactivation of NMDA receptors or non-NMDA receptors by excessive glutamate influx, calcium, or ROS overload and has been some of the well-studied molecular mechanisms conducive to the injury of white matter. Expression of glutamate receptors (GluR) and transporters (GLT1, EACC1, and GST) has significant influence in glial and axonal-mediated injury of premyelinated white matter during PVL and cerebral palsy. Predominantly, the central premyelinated axons express extensive levels of functional NMDA GluR receptors to confer ischemic injury to premyelinated white matter which in turn invoke defects in neural plasticity. Several underlying molecular mechanisms are yet to be unraveled to delineate the complete pathophysiology of these prenatal neurological diseases for developing the novel therapeutic modalities to mitigate pathophysiology and premature mortality of newborn babies. In this review, we have substantially discussed the above multiple pathophysiological aspects of white matter injury along with glial dynamics, and the pharmacotherapies including recent insights into the application of MSCs as therapeutic modality in treating white matter injury.

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Fig.1
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Fig. 3

source by transferring lactate and pyruvate into the periaxonal space through transporters such as MCT1 and MCT2. Any imbalance or failure in this energy supply can invoke ionic imbalance, followed by the depolarization, and heavy calcium influx through different channels to foster injury to the white matter structures. Calcium regulatory systems are significantly present in axons and glia to promote persistent calcium homeostasis through ‘plasmalemmal Ca2.1-ATPase’ NCX, (it can induce the efflux of high calcium), and intracellular calcium transporters (for example, axoplasmic reticulum [AR] Ca2+-ATPase [SERCA] and mitochondrial calcium homeostasis via uptake of Ca2+). Node of Ranvier is reported to be abundant in voltage gated-sodium channels (Nav1.6) to mediate spike current whereas the axolemma is composed of AMPA and kainate receptors as well as VGCC together coupled with internal calcium stores on AR to enhance calcium release. In addition, other metabotropic receptors such as mGluR and GABA-B and ATP receptors also exist. Interestingly, myelin expresses NMDA, AMPA, and purinergic receptors which are permeable to calcium, and these receptors could invoke the transfer of exosomes from oligodendrocytes to the growing axons. Ion-coupled transmitters , viz. glut (glutamate), glycine (glyT), and norepinephrine (NET) which are reported to be  modulated in terms of their release  according to the pathological condition. MCT, monocarboxylate transporters

Fig. 4

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Abbreviations

OGD:

Oxygen glucose deprivation

WMI:

White matter injury

PVL:

Periventricular leukomalacia

LPS:

Lipopolysaccharide

IGF-1:

Insulin-like growth factor-1

EAATs:

Excitatory amino acid transporters

RON:

Rat optic nerve

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Funding

This study was supported by National Natural Science Foundation of China (No. 81700729).

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Author notes

  1. Vladimir N. Nikolenko & Kirill V. Bulygin

    Present address: Department of Human Anatomy, I. M. Sechenov First Moscow State Medical University (Sechenov University), St. Trubetskaya, 8, bld. 2, Moscow, 119991, Russia

Authors and Affiliations

  1. Cancer Center, Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, People’s Republic of China

    Narasimha M. Beeraka MRes, PhD, Junqi Liu & Ruitai Fan MD PhD

  2. Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education and Research (JSS AHER), Mysuru, Karnataka, India

    Narasimha M. Beeraka MRes, PhD, M. V. Greeshma & Chinnappa A. Uthaiah

  3. Department of Human Anatomy, I. M. Sechenov First Moscow State Medical University (Sechenov University), St. Trubetskaya, 8, bld. 2, Moscow, 119991, Russia

    Narasimha M. Beeraka MRes, PhD & Mikhail Y. Sinelnikov

  4. Department of Pharmaceutical Chemistry, JSS Pharmacy College, Mysuru, Karnataka, India

    P. R. Hemanth Vikram

  5. Faculty of Medicine, Benghazi University, Benghazi, Libya

    Tahani Huria

  6. Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, LE1 7RH, UK

    Tahani Huria

  7. Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER-Guwahati), SilaKatamur (Halugurisuk), Changsari, Kamrup, 781101, Assam, India

    Pramod Kumar

  8. Department of Normal and Topographic Anatomy, Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, Russia

    Vladimir N. Nikolenko

  9. Research Institute of Human Morphology, 3 Tsyurupy Street, Moscow, 117418, Russian Federation

    Mikhail Y. Sinelnikov

  10. Discipline of Health Sciences, College of Nursing and Health Sciences, Flinders University, Bedford Park, South Australia, 5042, Australia

    Olga Sukocheva

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  1. Narasimha M. Beeraka MRes, PhD
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  2. P. R. Hemanth Vikram
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Contributions

Narasimha M. Beeraka (NMB), Hemanth Vikram (HV), Greeshma M V (GMV), Tahani Huria (TH), Junqi Liu (JL), Ruitai Fan (RF), Pramod Kumar (PK), Chinnappa A Uthaiah (CAU), Vladimir N. Nikolenko (VNN), Kirill V Bulygin (KVB), Mikhail Y Sinelnikov (MYS), and Olga Sukocheva (OS) contributed conceptualized, written and performed the formal analysis. NMB, OS, and MYS proofread the manuscript. All authors have reviewed and approved the manuscript before submission.

Corresponding author

Correspondence to Ruitai Fan MD PhD.

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Beeraka, N.M., Vikram, P.R.H., Greeshma, M.V. et al. Recent Investigations on Neurotransmitters’ Role in Acute White Matter Injury of Perinatal Glia and Pharmacotherapies—Glia Dynamics in Stem Cell Therapy. Mol Neurobiol 59, 2009–2026 (2022). https://doi.org/10.1007/s12035-021-02700-7

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