Overview of Dual-Acting Drug Methotrexate in Different Neurological Diseases, Autoimmune Pathologies and Cancers

Abstract

Methotrexate, a structural analogue of folic acid, is one of the most effective and extensively used drugs for treating many kinds of cancer or severe and resistant forms of autoimmune diseases. In this paper, we take an overview of the present state of knowledge with regards to complex mechanisms of methotrexate action and its applications as immunosuppressive drug or chemotherapeutic agent in oncological combination therapy. In addition, the issue of the potential benefits of methotrexate in the development of neurological disorders in Alzheimer's disease or myasthenia gravis will be discussed.

Keywords: Alzheimer’s disease; anticancer drug; disease modifying anti-rheumatic drug; immunosuppressive drug; methotrexate; myasthenia gravis.

Figure 1

Structure of folic acid and its derivatives - aminopterin and methotrexate.

Figure 2

Scheme of mechanism of methotrexate action. MTX—methotrexate; MTX_Glu—polyglutamated methotrexate; FRs—folate receptors; RFC₁—reduced folate carrier 1; FPGS—folylpolyglutamyl synthase; DHF—dihydrofolate; DHFR—dihydrofolate reductase; THF—tetrahydrofolate; dUMP—deoxyuridine monophosphate; TYMS—thymidylate synthase; dTMP—deoxythymidine monophosphate; DNA—deoxyribonucleic acid; RNA—ribonucleic acid; AICAR—5-aminoimidazole-4-carboxamide ribonucleotide; AICART—5-aminoimidazole-4- carboxamide ribonucleotide transformylase; FAICAR—5-formamidoimidazole-4-carboxamide ribonucleotide; IMP—inosine monophosphate; GMP—guanosine monophosphate; AMPDA—adenosine monophosphate deaminase; ADA—adenosine deaminase; AMP—adenosine monophosphate; CD73—ecto-5′-nucleotidase; A₁, A_2A, A_2B or A₃—adenosine receptors. Green arrows represent stimulation, red arrows and sticks represent inhibition, blue arrows represent biochemical conversion, yellow arrows represent migration.