Ganoderma Lucidum Triterpenoids Improve Maternal Separation-Induced Anxiety- and Depression-like Behaviors in Mice by Mitigating Inflammation in the Periphery and Brain

Abstract

Although early life stress (ELS) can increase susceptibility to adulthood psychiatric disorders and produce a greater inflammatory response in a stressful event, targeted preventive and therapeutic drugs still remain scarce. Ganoderma lucidum triterpenoids (GLTs) can exert anti-inflammatory effects in the periphery and central nervous systems. This study employed a combined model of “childhood maternal separation + adulthood sub-stress” to explore whether GLTs may alleviate anxiety- and depression-like behaviors in male and female mice by mitigating inflammation. Male and female pups were separated from their mothers for four hours per day from postnatal day 1 (PND 1) to PND 21; starting from PND 56, GLTs were administered intraperitoneally once daily for three weeks and followed by three days of sub-stress. Results showed that maternal separation increased the anxiety- and depression-like behaviors in both male and female mice, which disappeared after the preemptive GLTs treatment (40 mg/kg) before adulthood sub-stress. Maternal separation up-regulated the pro-inflammatory markers in the periphery and brain, and activated microglia in the prefrontal cortex and hippocampus. All the abnormalities were reversed by GLTs administration, with no adverse effects on immune organ indices, liver, and renal function. Our findings suggest that GLTs can be a promising candidate in treating ELS-induced psychiatric disorders.

Early life adversity as a risk factor for cognitive impairment and Alzheimer’s disease

“…Of note, these deficits were not observed in Nlrp3-/- mice or animals treated with an NLRP3 inhibitor, suggesting the critical involvement of NLRP3 inflammasome in stress-driven inflammation [ 155 ]. Similarly, the expression of pro-inflammatory factors was elevated in animals exposed to neonatal maternal separation, which was accompanied by memory impairment [ 156 , 157 ]. Furthermore, in APP/PS1 mice, LBN exposure led to lasting alterations in inflammation response, including increased hippocampal interleukin-1β expression and microglial activation, coinciding with accelerated disease progression [ 76 ].…”

Neuroprotective, neurogenic, and anticholinergic evidence ofGanoderma lucidumcognitive effects: Crucial knowledge is still lacking

“…Effects of Ganoderma lucidum on cognitive impairments elicited by models explored in articles found in this review. AChE, acetylcholinesterase; AKT, protein kinase B; BDNF, brain‐derived neurotrophic factor; CAT, catalase; CREB, cAMP response element‐binding protein; ERK, extracellular signal‐regulated kinase; GPx, glutathione peroxidase; GSH‐Px, plasma glutathione peroxidase; H 2 O 2 , hydrogen peroxide; JNK, c‐Jun N‐terminal kinase; MEK, ERK kinase; Nox, NADPH oxidase enzyme; Nrf, nuclear factor erythroid‐related factor; PI3K, phosphatidylinositol 3‐kinase; RAGE, receptor for advanced glycation end‐products; RAS, rat sarcoma virus; SOD, superoxide dismutase 19,20,25,28–30,32,35,42,46,50,59–64 . [Color figure can be viewed at wileyonlinelibrary.com]…”

“…Electrocardiograms, complete blood counts, blood chemistry analysis, immune status, as well as liver monitoring, renal toxicity, inflammation, and DNA damage/toxicity markers were evaluated, in which adverse effects were not observed. 75,85,86 Unfortunately, scarce 11,19,20,22,[24][25][26][28][29][30]32,35,36,40,42,46,50,54,[59][60][61][62][63][64][71][72][73][74][75][76][77][78][79][80][81][82] [Color figure can be viewed at wileyonlinelibrary.com] Assessment Scale-Cognitive (ADAS-cog), which evaluates cognitive domains, including memory, language, praxis, and orientation; in World Health Organization Quality of Life questionnaire (WHOQOL-BREF), which measures life quality through physical, psychological, social relationships, environment, and overall quality of life; and in Neuropsychiatric Index (NPI), which measures the frequency and severity of behavioral symptoms. 4,87 The authors suggest that such treatment requires an additional period of G. lucidum administration to obtain significant improvements.…”

“…19,29 Histologically, G. lucidum triterpenes reduce astrocyte activation and neuron degeneration in the hippocampus, which plays a pivotal role in the cognition domain (Figure 2). 29 Mi et al 64 reported that G. lucidum triterpenes (40 mg/kg, i.p., for 21 days) modulate central and peripheral inflammation, consisting of the mechanism to prevent anxiety-and depressive-like behavior in animal models at adult age, previously subjected to maternal separation and subacute stress. According to these results, early life stress increased susceptibility to an emotional imbalance in adult life.…”

Molecular mechanisms of the chemical constituents from anti-inflammatory and antioxidant active fractions of Ganoderma neo-japonicum Imazeki

“…In addition, some Ganoderma triterpenes exert anti-inflammatory effects by blocking the phosphorylation of p38 to inhibit the MAPK pathway ( Su et al, 2020 ; Xu et al, 2021 ). Recent studies have proved that Ganoderma lucidum triterpenoids can also play a pharmacological role in the peripheral and central nervous system, alleviate anxiety and depression like behavior of mice by reducing inflammation ( Mi et al, 2022 ), and reduce neuronal apoptosis and neuro-inflammation in Alzheimer's disease mice ( Yu et al, 2020 ; Y. Zhang et al, 2021 ).…”