Abstract
Neurocognitive deficits are serious sequelae that follow cranial irradiation used to treat patients with medulloblastoma and other brain neoplasms. Cranial irradiation causes apoptosis in the subgranular zone of the hippocampus leading to cognitive deficits. Valproic acid (VPA) treatment protected hippocampal neurons from radiation-induced damage in both cell culture and animal models. Radioprotection was observed in VPA-treated neuronal cells compared to cells treated with radiation alone. This protection is specific to normal neuronal cells and did not extend to cancer cells. In fact, VPA acted as a radiosensitizer in brain cancer cells. VPA treatment induced cell cycle arrest in cancer cells but not in normal neuronal cells. The level of anti-apoptotic protein Bcl-2 was increased and the pro-apoptotic protein Bax was reduced in VPA treated normal cells. VPA inhibited the activities of histone deacetylase (HDAC) and glycogen synthase kinase-3β (GSK3β), the latter of which is only inhibited in normal cells. The combination of VPA and radiation was most effective in inhibiting tumor growth in heterotopic brain tumor models. An intracranial orthotopic glioma tumor model was used to evaluate tumor growth by using dynamic contrast-enhanced magnetic resonance (DCE MRI) and mouse survival following treatment with VPA and radiation. VPA, in combination with radiation, significantly delayed tumor growth and improved mouse survival. Overall, VPA protects normal hippocampal neurons and not cancer cells from radiation-induced cytotoxicity both in vitro and in vivo. VPA treatment has the potential for attenuating neurocognitive deficits associated with cranial irradiation while enhancing the efficiency of glioma radiotherapy.
Highlights
Radiotherapy, the clinical application of ionizing radiation, is a crucial treatment option in modern cancer therapy in addition to surgery and systemic therapy
Apoptosis within the subgranular zone was determined by staining the hippocampal sections with a TUNEL kit, and the TUNEL positive cells (TPC) were counted (Figs. 1A & 1B)
Mice treated with Valproic acid (VPA) prior to 7Gy irradiation had significantly fewer TPC compared to mice irradiated with 7 Gy (P < 0.001; Fig. 1B), indicating that VPA treatment protected the mouse hippocampus from radiation-induced apoptosis
Summary
Radiotherapy, the clinical application of ionizing radiation, is a crucial treatment option in modern cancer therapy in addition to surgery and systemic therapy. This is corroborated by the fact that more than 60% of all cancer patients receive radiotherapy [1, 2]. The pathogenesis of radiation-induced neurocognitive deficits involves apoptosis of neuroproliferative cells in the subgranular zone of the hippocampus, a region in the brain vital for learning and memory [6,7,8,9,10,11]. Minocycline ameliorated cognitive impairment induced by WBRT in animal models [21]
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