Whole-brain irradiation differentially modifies neurotransmitters levels and receptors in the hypothalamus and the prefr
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RESEARCH
Whole‑brain irradiation differentially modifies neurotransmitters levels and receptors in the hypothalamus and the prefrontal cortex Javier Franco‑Pérez1, Sergio Montes2, Josué Sánchez‑Hernández1 and Paola Ballesteros‑Zebadúa3*
Abstract Background: Whole-brain radiotherapy is a primary treatment for brain tumors and brain metastasis, but it also induces long-term undesired effects. Since cognitive impairment can occur, research on the etiology of secondary effects has focused on the hippocampus. Often overlooked, the hypothalamus controls critical homeostatic functions, some of which are also susceptible after whole-brain radiotherapy. Therefore, using whole-brain irradiation (WBI) in a rat model, we measured neurotransmitters and receptors in the hypothalamus. The prefrontal cortex and brainstem were also analyzed since they are highly connected to the hypothalamus and its regulatory processes. Methods: Male Wistar rats were exposed to WBI with 11 Gy (Biologically Effective Dose = 72 Gy). After 1 month, we evaluated changes in gamma-aminobutyric acid (GABA), glycine, taurine, aspartate, glutamate, and glutamine in the hypothalamus, prefrontal cortex, and brainstem according to an HPLC method. Ratios of Glutamate/GABA and Glutamine/Glutamate were calculated. Through Western Blott analysis, we measured the expression of GABAa and GABAb receptors, and NR1 and NR2A subunits of NMDA receptors. Changes were analyzed comparing results with sham controls using the non-parametric Mann–Whitney U test (p Gln > GABA. On the contrary, the Gly content was the lowest (Fig. 1a). We further examined the Gln/Glu and Glu/GABA ratios since the balance between inhibition and excitation is essential for the neurotransmission in the brain. Therefore, radiation did not induce significant changes in the Gln/Glu ratio (Fig. 1b); however, there was a significant increase of the Glu/GABA ratio in the hypothalamus after WBI (p = 0.004) (Fig. 1c). By contrast, in the prefrontal cortex, an alteration of the glutamatergic transmission was observed, since excitatory neurotransmitters were increased 1 month after treatment. Figure 2a illustrates how levels of Glu
Franco‑Pérez et al. Radiat Oncol
(2020) 15:269
Page 4 of 13
Fig. 1 Neurotransmitters analysis in the hypothalamus 1 month after sham (white bars) or treatment with 11 Gy whole-brain irradiation (black bars). The analyzed region is indicated in a Paxinos and Watson diagram [21]. a The concentration (μMol/g of fresh tissue) of the following amino acids: Asp, Glu, Gln, Gly, Tau, and GABA. Glutamine/Glutamate and Glutamate/GABA ratios are showed in b, c, respectively. Data are expressed as means ± SEM. Groups were statistically compared using the Mann–Whitney U test *p ≤ 0.05
Franco‑Pérez et al. Radiat Oncol
(2020) 15:269
Page 5 of 13
Fig. 2 Neurotransmitter levels in the prefrontal cortex 1 month after sham (white bars) or treatment with 11 Gy whole-brain irradiation (black bars). The analyzed region is indicated in a Paxinos and Watson diagram [21]. a
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