Abstract
Despite advancements in the radiotherapeutic management of brain malignancies, resultant sequelae include persistent cognitive dysfunction in the majority of survivors. Defining the precise causes of normal tissue toxicity has proven challenging, but the use of preclinical rodent models has suggested that reductions in neurogenesis and microvascular integrity, impaired synaptic plasticity, increased inflammation, and alterations in neuronal structure are contributory if not causal. As such, strategies to reverse these persistent radiotherapy-induced neurological disorders represent an unmet medical need. AM251, a cannabinoid receptor 1 reverse agonist known to facilitate adult neurogenesis and synaptic plasticity, may help to ameliorate radiation-induced CNS impairments. To test this hypothesis, three treatment paradigms were used to evaluate the efficacy of AM251 to ameliorate radiation-induced learning and memory deficits along with disruptions in mood at 4 and 12 weeks postirradiation. Results demonstrated that acute (four weekly injections) and chronic (16 weekly injections) AM251 treatments (1 mg/kg) effectively alleviated cognitive and mood dysfunction in cranially irradiated mice. The beneficial effects of AM251 were exemplified by improved hippocampal- and cortical-dependent memory function on the novel object recognition and object in place tasks, while similar benefits on mood were shown by reductions in depressive- and anxiety-like behaviors on the forced swim test and elevated plus maze. The foregoing neurocognitive benefits were associated with significant increases in newly born (doublecortin+) neurons (1.7-fold), hippocampal neurogenesis (BrdU+/NeuN+mature neurons, 2.5-fold), and reduced expression of the inflammatory mediator HMGB (1.2-fold) in the hippocampus of irradiated mice. Collectively, these findings indicate that AM251 ameliorates the effects of clinically relevant cranial irradiation where overall neurological benefits in memory and mood coincided with increased hippocampal cell proliferation, neurogenesis, and reduced expression of proinflammatory markers.
Highlights
Every year, more than 150,000 cancer patients in the United States receive radiotherapy for primary and metastatic brain tumors (Owonikoko et al, 2014; Makale et al, 2017)
Consistent with these trends, we found that irradiated mice subjected to various AM251 treatments exhibited significant improvements in neurogenesis (2.5-fold), again coincident with enhanced behavioral performance
Our results add to a growing body of evidence suggesting that the adverse impact of cranial irradiation on multiple neurocognitive indices results in part, through the inhibition of neurogenesis and a persistent neuroinflammation (Monje and Palmer, 2003; Monje et al, 2007; Greene-Schloesser et al, 2012, 2013; Acharya et al, 2016; Hinkle et al, 2019)
Summary
More than 150,000 cancer patients in the United States receive radiotherapy for primary and metastatic brain tumors (Owonikoko et al, 2014; Makale et al, 2017). While the precise molecular pathways involved in radiation-induced normal tissue toxicities remain to be elucidated, altered hippocampal neurogenesis, elevated oxidative stress, and neuroinflammation most certainly play a role (Monje and Palmer, 2003; Monje et al, 2007; Greene-Schloesser et al, 2012, 2013; Oh et al, 2013). In efforts to provide some relief from the unintended neurocognitive complications arising from cranial radiotherapy, treatment plans incorporating hippocampal avoidance have become more commonplace. While such strategies have been shown to be beneficial (Gondi et al, 2014; Brown et al, 2020), a significant fraction of resultant radiation-induced deficits persist, leaving this as a largely unmet medical need. Given the paucity of effective treatment strategies for the long-term preservation of neurological health in brain cancer survivors, efforts to identify efficacious treatments able to ameliorate or prevent radiationinduced CNS toxicities remain a topical area of research
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