## 4 Discussion  
In the present study, we investigated whether GBT exerts effects on behavioral impairment induced by heat stress by inducing antifebrile effects in mice. This study also showed that ALRP has potent antipyretic properties, suppressing systemic inflammation after heat exposure. To reveal the anti-inflammatory effects of ALPR against heat stress, we demonstrated the downregulation of levels of IL-9, IL-13, PGE1, and PGE2 levels in the mouse hypothalamus, which resulted in the secretion of cortisol in mice. Thus, after treated with GBT, the amelioration of the HPA axis-mediated systemic inflammation appears to be mediated by the effects of ALRP at least. Figure 4: Inhibitory effect of ALRP on increases of IL-9, IL-13 and ratio of PGE2/PGE1. In hypothalamus of mice after heat exposure, the presences of IL-9 (**A**), IL-13 (**B**) and ratio of PGE2/PGE1 (**C**) were determined using sandwich ELISA kit (n = 6 per group). Values are expressed as means \(\pm\) SEM. * \(p\) \(<\) 0.05 and *** \(p\) \(<\) 0.001 as compared with the control group. # \(p\)\(<\) 0.05, ## \(p\)\(<\) 0.01 and ## \(p\)\(<\) 0.001 as compared with the heat-stressed vehicle-treated group. ALRP; Aconiti Lateralis Radix Preparata. IL-9; interleukin-9. IL-13; interleukin-13. PGE1; prostaglandin 1. PGE2; prostaglandin 2. Figure 5: Suppressive effect of ALRP on heat exposure-induced increase of cortisol secretion (n = 6 per group). Values are expressed as means \(\pm\) SEM. *** \(p\) \(<\) 0.001 as compared with the control group. ### \(p\)\(<\) 0.001 as compared with the heat-stressed vehicle-treated group. The immune inflammatory response is closely associated with stress response. Activation of the HPA axis produces marked inhibitory effects on the immune inflammatory response, as virtually all the components of the immune response are inhibited by cortisol, an important factor in glucocorticoid hormone synthesis in the hypothalamus. Numerous studies have identified the central pathways mediating the stress response by mapping neuronal activation using c-fos as a dependable indicator [16; 17]. In addition, intense expression of c-fos in the hypothalamus is closely related to corticotropin-releasing factor (CRF), which activates the release of corticosterone [17]. Corticosterone secretion is related to an increase in the synthesis of the proinflammatory-tory prostaglandin PGE2 in the brain. In the central nervous system, PGE2 has been related to the control of neuroinflammation-matory processes, synaptic transmission, brain plasticity, regulation of fever, and the HPA axis activation [18]. In turn, cytokines, such as IL-9 and IL-13, also stimulate the HPA axis, which can influence virtually every pathophysiologic domain relevant to depression, including neuroendocrine function, neurotransmitter metabolism, regional brain activity, and ultimately, behavior [19]. In this study, we evaluated locomotive activities reduced by heat stress, which could be the phenotype underlying depressive behavior, and studied the associated effects of GBT. The effects of ALRP on thermal stress-induced inflammation have been previously reported. Studies have investigated the effects of ALRP on cold stress-induced homeostasis dysregulation according to its traditional functions in alleviating energy metabolism [20]. In addition, reports have identified regulatory mechanisms, such as enhancement of natural killer cell activity and normalization of the HPA axis [13; 14]. According to [PERSON] et al., ALRP is regulated in the mouse hypothalamus, which resulting in the inhibition of systemic inflammation, including neuroinflammation [13]. Interestingly, these anti-inflammatory effects were only observed in thermal stress-induced thermo-dysregulation. This indicates that ALRP inhibits the production of cytokines and pro-inflammatory factors by regulating the HPA axis. Thus, further studies using other inflammatory models are needed to demonstrate the effects of ALRP on inflammation and elucidate its precise mechanisms.