title: Memantine protects rats treated with intrathecal methotrexate from developing spatial memory deficits.
abstract: OBJECTIVE
  To test whether memantine can prevent methotrexate-induced cognitive deficits in a preclinical model.
  
  
  METHODS
  After noting that methotrexate exposure induces prolonged elevations of the glutamate analog homocysteic acid (HCA) within cerebrospinal fluid, we tested whether intrathecal injection of HCA would produce memory deficits similar to those observed after intrathecal methotrexate. We then tested whether memantine, an antagonist of the N-methyl-d-aspartate (NMDA) subclass of glutamate receptors, could protect animals treated with clinically relevant doses of intrathecal methotrexate against developing memory deficits. Finally, we asked whether memantine affected this pathway beyond inhibiting the NMDA receptor by altering expression of the NMDA receptor or affecting concentrations of HCA or glutamate within the central nervous system.
  
  
  RESULTS
  Four intrathecal doses of methotrexate induced deficits in spatial memory, persisting at least one month following the final injection. Intrathecal HCA was sufficient to reproduce this deficit. Concurrent administration of memantine during the period of methotrexate exposure was protective, decreasing the incidence of methotrexate-induced spatial memory deficits from 56% to 20% (P < 0.05). Memantine neither altered expression of NMDA receptors within the hippocampus nor blunted the methotrexate-induced increases in glutamate or HCA.
  
  
  CONCLUSIONS
  Excitotoxic glutamate analogs including HCA contribute to cognitive deficits observed after intrathecal methotrexate. Memantine, an NMDA receptor antagonist, reduces the incidence of cognitive deficits in rats treated with intrathecal methotrexate, and may therefore benefit patients with cancer receiving similar treatment.
authors.affiliation: Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York 10461, USA. Peter.Cole@Einstein.YU.edu
authors.forename: Peter D
authors.initials: PD
authors.lastname: Cole
authors.forename: Veena
authors.initials: V
authors.lastname: Vijayanathan
authors.forename: Nafeeza F
authors.initials: NF
authors.lastname: Ali
authors.forename: Mark E
authors.initials: ME
authors.lastname: Wagshul
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Tanenbaum
authors.forename: Jeremy
authors.initials: J
authors.lastname: Price
authors.forename: Vidhi
authors.initials: V
authors.lastname: Dalal
authors.forename: Maria E
authors.initials: ME
authors.lastname: Gulinello
mesh_terms: D000818:Animals; D003071:Cognition / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000009:adverse effects; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007278:Injections, Spinal; D008297:Male; D008559:Memantine / Q000008:administration & dosage / Q000494:pharmacology*; D008569:Memory Disorders / Q000139:chemically induced* / Q000188:drug therapy*; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D008559:Memantine; D008727:Methotrexate