Caffeine mitigates neuroinflammation and behavioral deficits induced by brain irradiation in mice

Radiotherapy, a standard treatment for brain tumors, may induce cognitive deficits and neuroinflammatory responses, including increased pro-inflammatory cytokines, microglial and astrocytic reactivity, and alterations in neuronal markers. Caffeine, a widely consumed psychostimulant with reported anti-inflammatory and neuroprotective properties, has been proposed as a potential modulator of these effects. This study evaluated whether continuous caffeine consumption is associated with attenuation of neuroinflammation, glial alterations, and behavioral impairments induced by brain irradiation in mice.

Male C57BL/6J mice were assigned to four groups: non-irradiated control (C), irradiated (I), non-irradiated treated with caffeine (Ca), and irradiated treated with caffeine (ICa). Caffeine (0.25 g/L) was administered ad libitum for 94 days. Whole-brain irradiation (10 Gy) was delivered using a SARRP platform. Behavioral performance was assessed using the open-field, and object location memory tests. Immunofluorescence analyses for TNF-α, Iba1, GFAP, and NeuN were conducted in hippocampal subregions, and plasma TNF-α levels were quantified by ELISA.

Irradiation impaired spatial memory, reduced locomotor activity, increased hippocampal TNF-α and GFAP immunolabeling, decreased Iba1 immunoreactivity, and reduced NeuN-positive neurons. In irradiated mice, caffeine consumption was associated with improved memory performance, preservation of locomotor activity, and attenuation of radiation-related changes in TNF-α, GFAP, Iba1, and NeuN immunolabeling. Plasma TNF-α levels did not differ across groups.

Continuous caffeine consumption was associated with reduced neuroinflammatory markers and modified glial and neuronal immunolabeling patterns, coinciding with improved behavioral outcomes in irradiated mice. This effect is interpreted as post-exposure mitigation rather than true regeneration.