Neuropharmacological effects of methotrexate perfused through the cerebrospinal fluid system of the rhesus monkey

Thirteen adult Rhesus monkeys were repeatedly perfused through the ventriculocisternal or ventriculolumbar spaces with Elliott's B solution containing various concentrations of methotrexate (MTX) and trace amounts of [3H]MTX and [carboxy-14C]inulin. The concentrations of MTX ranged from 4.8 to 0.15 mg/ml representing perfusion dosages of 551 mg/sq m to 16 mg/sq m. The average steady-state concentration out-concentration in (Co/Ci) value for MTX was 0.78 +/- 0.04 for the ventriculocisternal and 0.66 +/- 0.01 for the ventriculolumbar routes. MTX treatments did not significantly affect mean inulin steady-state Co/Ci values or CSF formation rate. With the exception of a monkey perfused with MTX at an inflow concentration of 4.8 mg/ml, body weight, food intake, and urine output, analyzed at weekly intervals, generally were not remarkably affected by MTX perfusions. In five monkeys perfused with MTX in concentrations of 4.8 to 0.6 mg/ml, gross neurological toxicity was observed, principally in the form of seizures and hypokinesia during perfusion series with occasional residual motor deficit. Significant cerebral damage was associated with the brains of two monkeys perfused with MTX at concentrations of 2.4 and 0.6 mg/ml and two monkeys perfused at concentrations of 1.2 and 0.3 mg/ml; there of the four animals displayed signs of gross neurotoxicity, and two animals developed permanent motor deficits. However, the extent to which neurotoxic signs could be attributed solely to MTX was difficult to judge because some changes in central nervous system morphology were associated with the mechanical aspects of the procedure. Overall behavioral performance as measured by a visual pattern discrimination reinforced by avoidance or escape from an electric shock was not significantly affected by repeated perfusions of MTX (0.6 mg/ml) in two monkeys not otherwise studied in detail.