Effect of Methotrexate on Local Cerebral Blood Flow in Conscious Rats

Abstract

Abstract-The effect of methotrexate (MTX) on local cerebral blood flow (I-CBF) was studied with autoradiographic[14C]-iodoantipyrine methods in normal con scious rats. I-CBF was reduced by 30-57% in the rats given MTX (100 mg or 200 mg/body) as compared to that in the saline injected control group, but no dose dependent effect was observed. The mechanism of I-CBF reduction by MTX was discussed.The administration of high-dose metho trexate (MTX) is now widely used in the treatment of osteogenic sarcoma and child hood brain tumors (1). However, this treat ment may lead to severe neurotoxicity such as acute encephalopathy (2). To examine the mechanisms of MTX neurotoxicity, Phillips et al. (3) developed a model of acute high-dose MTX encephalopathy in the rat and found that MTX reduced cerebral glucose me tabolism in the absence of systemic organ toxicity. Silverstein and Johnston (4) re ported that MTX produced histopathologic changes in the brain and it disrupted the syntheses of some neurotransmitters, or af fected the metabolism in the rat. However, the effect of MTX on the cerebral circulation has not been studied. In the present study, we have examined the effect of MTX on local cerebral blood flow (I-CBF) in normal con scious rats.CBF was measured by an autoradiographic technique (5). Male Sprague-Dawley rats weighing from 300 to 460 g were anesthetized with halothane and N20, and polyethylene catheters were inserted into the femoral artery and vein for arterial blood sampling and for drug infusion, respectively. The rats were then immobilized by loosely fitted plaster casts. After recovering from anesthesia, low dose MTX (LD-MTX) rats (n=5) were infused intravenously with 100 mg of MTX in 6 ml of saline for 2 hr. Similarly, high dose MTX (HD MTX) rats (n=4) were infused with 200 mg of MTX, and control rats (n=4) were infused with 6 ml of saline. For the measurement of I-CBF, [14C]-iodoantipyrine was infused intravenously for 1 min, and the animals were then sacrificed by intravenous injection of 1 ml of saturated KCI solution. During the 1 min infusion period, 18-20 arterial samples were collected for measurement of 14C activity. The tissue activity was determined in 33 defined brain structures with quantitative autoradiography. Plasma MTX concentrations were measured 2 hr after the start of MTX infusion by a dihydrofolate reductase inhi bition assay (Methotrexate® kit, Lederle). Mean arterial blood pressure (MABP) was continuously monitored, and PaC02, Pa02, pH and hematocrit values were measured im mediately before I-CBF measurement. Sta tistically significant differences were deter mined using one-way analysis of variance

Methotrexate reduces hippocampal blood vessel density and activates microglia in rats but does not elevate central cytokine release

“…MTX was infused into the femoral vein of conscious male SpragueDawley rats for 2 h and cerebral blood flow was measured with [ 14 C]iodoantipyrine. Compared to control conditions, MTX reduced cerebral blood flow in a number of regions, including the hippocampus and frontal cortex [23]. Our PET results show a transient decrease in FDG uptake in the hippocampal region.…”

MR perfusion, diffusion and BOLD imaging of methotrexate‐exposed swine brain

“…Earlier results of human brain perfusion in SPECT showed defects in the cortical areas and the basal ganglia (15,20,21). Also, a brain perfusion study in rats with PET indicated that CBF reduced in all brain regions after MTX infusion (16). In this work, selected ROIs (the cortex, the sub-cortex, the thalamus, or deep structures) were taken into account as preferable areas of the MTX exposure-induced changes in rCBF or white matter.…”

“…CMR glu is found to reduce 20%-40% due to MTX exposure (12)(13)(14). Exposure to MTX may cause either local (cortical, sub-cortical, periventricular) or diffuse white matter changes (hypo/hyperintensity) in the anatomic MRI or computed tomography (17)(18)(19)(20); however, functional changes in brain perfusion have only been studied in SPECT and PET (15,16,20,21).…”

“…MTX induces deficits in brain perfusion in several brain areas detected with Single Photon Emission Computed Tomography (SPECT) and positron emission tomography (PET) studies (15,16). Also, MTX may sometimes induce white matter changes in the anatomic MRI (17)(18)(19).…”

Topical application of methotrexate for inhibition of corneal angiogenesis

“…MTX reduces the requirement for systemic steroids and stabilizes or decreases the level of intraocular inflammation. In addition to its effect as immunomodulatory drug in rheumatoid disease, studies in other fields have reported, for example, vascular occlusion after intraarterial therapy with MTX [33] and reduction of local cerebral blood flow by MTX [30], suggesting a potential use of MTX as antiangiogenic agent.…”