Liposomal Cytarabine Induces Less Neurocognitive Dysfunction Than Intrathecal Methotrexate in an Animal Model

Abstract

Liposomal cytarabine is currently being tested clinically as an alternative to intrathecal (IT) methotrexate (MTX) for preventing relapse within the central nervous system among patients with acute lymphoblastic leukemia. To compare the toxicity and cognitive deficits caused by IT MTX versus liposomal cytarabine, juvenile Long Evans rats were treated with IT injections of MTX 1 mg/kg×4 doses over 8 days, or liposomal cytarabine 0.8 mg once. Mean concentrations of free cytarabine in cerebrospinal fluid remained above the cytotoxic threshold of 0.4 μM for 2 weeks after dosing. Animals treated with liposomal cytarabine exhibited normal recognition and spatial memory 4 weeks after injection. In contrast, exposure to IT MTX led to impaired cognitive function. In addition, mean hematocrit on day 11 was significantly lower in the MTX-treated animals (30.8%; 95% confidence interval, 27.0%-34.7%; n=6) compared with that in the liposomal cytarabine-treated animals (39.5%; 95% confidence interval, 38.4%-40.6%; n=6; P<0.0001). Our data suggest that liposomal cytarabine induces fewer neurocognitive deficits and less acute hematologic toxicity compared with IT MTX. Liposomal cytarabine may therefore have therapeutic advantages over IT MTX, if it is equally effective in preventing relapse.

Methotrexate causes persistent deficits in memory and executive function in a juvenile animal model

“…Behavioral assessments of cognitive function were conducted at two time points (Figure 1) in order to assess acute effects (9 weeks of age; 1 week after the last methotrexate exposure and persistent effects (15 weeks of age; 8 weeks after the last methotrexate exposure). The battery included the following: open field (OF), object placement (OP) (a.k.a object location) and novel object recognition (NOR)(Ennaceur and Meliani, 1992), conducted as previously published (Li et al, 2010; Thomsen et al, 2017) and described briefly below. A modified set shifting assay, described below, was done at a single time point (16–19 weeks of age; 9–12 weeks following the last methotrexate exposure).…”

“…The pathophysiology of methotrexate-induced neurotoxicity is multifactorial and incompletely defined (Cole and Kamen, 2006; Vezmar et al, 2003). Animal modeling has shown promise in elucidating the mechanisms underlying cognitive dysfunction following both systemic and intrathecal administration of methotrexate (Li et al, 2010; Seigers et al, 2009; Thomsen et al, 2017). Data from these models suggest methotrexate can induce deficits through induction of oxidative stress (Caron et al, 2009), modulation of the immune system (Cutolo et al, 2001; Phillips et al, 2003; Zhang et al, 2009), inhibition of neurogenesis (Seigers et al, 2009), altered neurotransmission through the NMDA receptor (Cole et al, 2013; Vijayanathan et al, 2011) and/or induction of structural brain alterations (Seigers et al, 2009).…”