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Glutamate in Multiple Sclerosis: From Pathophysiology to Treatments

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Glutamate and Neuropsychiatric Disorders

Abstract

Multiple sclerosis (MS) is an autoimmune disease typified by overt demyelination and inflammation that develop in selected regions of the central nervous system (CNS). Besides these signs, a diffuse loss of synaptic contacts, axonal pruning and astrocytosis are also observed, that in general correlate with the dysregulation of the glutamatergic system and with the onset of neurological symptoms. Concomitantly to the synaptic derangements, impaired glutamate homeostasis also dysregulates the immunocompetent responses, impairing the functional cross-talk between the immune system and the CNS. The study of the glutamatergic system therefore emerges as an important issue for deciphering the cellular events at the basis of MS as it would permit the proposal of new appropriate pharmacological interventions for the cure of the pathology. The chapter describes recent advances in basic research, preclinical and clinical studies concerning the impact of altered glutamate homeostasis in the course of the disease, as well as in the innovative strategies that would permit the restoration of central glutamatergic transmission.

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Abbreviations

2-AG:

2-arachidonoylglycerol

2-PMPA:

2-(phosphonomethyl) pentanedioic acid

AC:

Adenylyl cyclase

CB1 receptors:

Cannabinoid receptors type 1

CNS:

Central nervous system

d.p.i.:

Days post immunization

DMDs:

Disease-modifying drugs

EAAT:

Excitatory amino acid transporter

EAE:

Experimental autoimmune encephalomyelitis

EC:

Endogenous cannabinoids

EPSCs:

Excitatory postsynaptic currents

FAAH:

Fatty acid amide hydrolase

GCPII:

Glutamate carboxypeptidase II

GDH:

Glutamate dehydrogenase

GLS:

Glutaminase

GOT:

Glutamate-oxaloacetate transaminase

GPT:

Glutamate-pyruvate transaminase

GS:

Glutamine synthase

HCAR2:

Hydroxycarboxylic acid receptor 2

IPSCs:

Inhibitory postsynaptic currents

IS:

Immune system

KA:

Kynurenic acid

KP:

Kynurenine pathway

LTD:

Long-term depression

LTP:

Long-term potentiation

MBP:

Myelin basic protein

MGL:

Monoacylglycerol lipase

mGlu receptor:

Metabotropic glutamate receptor

MOG:

Myelin oligodendrocyte glycoprotein

MS:

Multiple sclerosis

MUNC-18:

Mammalian uncoordinated-18

NAA:

N-acetyl-aspartate

NAALADase:

N-acetylated-alpha-linked acidic dipeptidase

PKA:

Protein kinase A

PLP:

Proteolipid protein

PPMS:

Primary progressive multiple sclerosis

QA:

Quinolinic acid

RMI:

Resonance imaging

RRMS:

Relapsing-remitting multiple sclerosis

SPMS:

Secondary progressive multiple sclerosis

T:

Tryptophan

TMS:

Transcranial magnetic stimulation

xCT:

Cystine/glutamate antiporter

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Authors and Affiliations

  1. Department of Pharmacy (DIFAR), University of Genoa, Genoa, Italy

    Anna Pittaluga & Guendalina Olivero

  2. IRCCS Ospedale Policlinico San Martino, Genoa, Italy

    Anna Pittaluga

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  1. Anna Pittaluga
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  2. Guendalina Olivero
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Correspondence to Anna Pittaluga .

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  1. Heruka Lifescience and Health Innovations, Belgrade, Serbia

    Zoran M. Pavlovic

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Pittaluga, A., Olivero, G. (2022). Glutamate in Multiple Sclerosis: From Pathophysiology to Treatments. In: Pavlovic, Z.M. (eds) Glutamate and Neuropsychiatric Disorders. Springer, Cham. https://doi.org/10.1007/978-3-030-87480-3_15

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