International journal of radiation biology · 2025
Intranasal ketamine mitigates radiation-induced brain injury in a rabbit model by modulating ECM/PNN markers and neuroinflammation, with in vivo 1H-MR spectroscopy readouts.
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Erbas Oytun, Erdogan Mumin Alper, Ozkul Bahattin, Uyanikgil Yigit
Аннотация
INTRODUCTION: Radiation-induced brain injury causes significant neurotoxicity and cognitive dysfunction in patients undergoing radiotherapy for brain tumors. This study aimed to evaluate the neuroprotective effects of intranasal ketamine on radiation-induced brain injury, specifically focusing on its modulation of perineuronal networks (PNNs), extracellular matrix components, and neuroinflammation.
MATERIALS AND METHODS: Eighteen male New Zealand White Rabbits were divided into three groups: normal controls, irradiation (IR) with saline (IR + saline), and IR with ketamine (IR + ketamine). Whole-brain IR (20 Gy) was applied to the IR groups, and ketamine (2 mg/kg/day) was administered intranasally for 15 days. Biochemical markers, including malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), brain-derived neurotrophic factor (BDNF), ADAMTS4, and syndecan-1 levels, were measured. Histopathological analysis of hippocampal and cerebellar regions assessed neuronal survival and astrogliosis. Magnetic resonance spectroscopy (MRS) evaluated lactate and N-acetylaspartate (NAA) levels, reflecting metabolic and neuronal integrity.
RESULTS: Ketamine administration significantly reduced oxidative stress (MDA) and inflammatory markers (TNF-α) while restoring BDNF levels compared to the IR + saline group. ADAMTS4 and syndecan-1 levels were reduced, changes consistent with PNN-associated extracellular matrix dynamics, but without direct confirmation by core PNN markers such as aggrecan or WFA staining. Histopathology showed increased neuronal survival and decreased reactive astrogliosis in ketamine-treated groups. 1H-MRS provided supporting evidence for metabolic changes (↓lactate, ↑NAA) consistent with improved mitochondrial function and neuronal integrity.
CONCLUSION: Intranasal ketamine demonstrates significant neuroprotective effects in a radiation-induced brain injury model by reducing oxidative stress and inflammation, modulating extracellular matrix components, and preserving neuronal integrity. These findings highlight ketamine's potential as a therapeutic agent, although direct PNN markers and broader cytokine panels were not assessed. Overall, ketamine showed neuroprotective effects across biochemical, histological, and MRS-supported metabolic readouts.
MATERIALS AND METHODS: Eighteen male New Zealand White Rabbits were divided into three groups: normal controls, irradiation (IR) with saline (IR + saline), and IR with ketamine (IR + ketamine). Whole-brain IR (20 Gy) was applied to the IR groups, and ketamine (2 mg/kg/day) was administered intranasally for 15 days. Biochemical markers, including malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), brain-derived neurotrophic factor (BDNF), ADAMTS4, and syndecan-1 levels, were measured. Histopathological analysis of hippocampal and cerebellar regions assessed neuronal survival and astrogliosis. Magnetic resonance spectroscopy (MRS) evaluated lactate and N-acetylaspartate (NAA) levels, reflecting metabolic and neuronal integrity.
RESULTS: Ketamine administration significantly reduced oxidative stress (MDA) and inflammatory markers (TNF-α) while restoring BDNF levels compared to the IR + saline group. ADAMTS4 and syndecan-1 levels were reduced, changes consistent with PNN-associated extracellular matrix dynamics, but without direct confirmation by core PNN markers such as aggrecan or WFA staining. Histopathology showed increased neuronal survival and decreased reactive astrogliosis in ketamine-treated groups. 1H-MRS provided supporting evidence for metabolic changes (↓lactate, ↑NAA) consistent with improved mitochondrial function and neuronal integrity.
CONCLUSION: Intranasal ketamine demonstrates significant neuroprotective effects in a radiation-induced brain injury model by reducing oxidative stress and inflammation, modulating extracellular matrix components, and preserving neuronal integrity. These findings highlight ketamine's potential as a therapeutic agent, although direct PNN markers and broader cytokine panels were not assessed. Overall, ketamine showed neuroprotective effects across biochemical, histological, and MRS-supported metabolic readouts.