Elucidation of neuroprotective role of Hericium erinaceus in animal models of depression and cerebellar ataxia

Abstract

Depression is a severe neuropsychiatric disorder that affects more than 300 million people. It is one of the significant contributors to the global burden of diseases. Although there are many conventional antidepressants, their efficacies are barely adequate, and many have side effects. Therefore, the search for novel antidepressants that potentially has higher efficacy and less side effect is still needed. Hericium erinaceus is a medicinal mushroom that has reported to possess therapeutic potential for depression. This study investigated the antidepressant-like effects of H. erinaceus in restraint-stress induced model of depression. The results showed that 4-weeks of H. erinaceus treatment ameliorates depressive-like behaviours in mice subjected to 14-days of restraint stressed. Temozolomide, a neurogenesis blocker was used to evaluate if the behavioural responses are mediated through neurogenesis-dependent mechanisms. No significant differences were found between all the temozolomide experimental groups, implying that the administration of neurogenesis blocker has completely abolished the antidepressant-like effects of H. erinaceus. This result supported the hypothesis that the underlying mechanism of antidepressant effects by H. erinaceus is through neurogenesis-dependent mechanism. Furthermore, several neurogenesis-related gene and protein expressions including doublecortin, nestin, synaptophysin, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), phosphorylated extracellular signal-regulated kinase (pERK) and phosphorylated cAMP response element-binding protein (pCREB) were elevated after 4-weeks of H. erinaceus treatment. These results supported the hypothesis that H. erinaceus potentially rescue the behavioural despair through BDNF-TrkB-CREB signalling mechanism, eventually increases the hippocampal neurogenesis and lead to antidepressant-like effects. To further investigate the neuroprotective effects of H. erinaceus in neurodegenerative disease, 3-acetylpyridine (3AP)-induced animal model of cerebellar ataxia was used to investigate if H. erinaceus could rescue the motor coordination deficit by protecting the Purkinje cells in the cerebellum of ataxic rats. Cerebellar ataxia is a neurodegenerative disorder with no definitive treatment. Although several studies have demonstrated the neuroprotective effects of H. erinaceus (H. E.), its mechanisms in cerebellar ataxia remain largely unknown. Animals administered 3-AP injection exhibited remarkable impairments in motor coordination and balance. There were no significant effects of 25 mg/kg H.E. on the 3-AP treatment group compared to the 3-AP saline group. Interestingly, there was also no significant difference in the 3-AP treatment group compared to the non-3-AP control, indicating a potential rescue of motor deficits. The results revealed that 25 mg/kg H.E. normalised the neuroplasticity-related gene expression to the level of non-3-AP control. These findings were further supported by increased protein expressions of pERK1/2-pCREB-PSD95 as well as neuroprotective effects on cerebellar Purkinje cells in the 3-AP treatment group compared to the 3-AP saline group. In conclusion, the findings suggest that H. erinaceus potentially rescued behavioural motor deficits through the neuroprotective mechanisms of ERK-CREB-PSD95 in an animal model of 3-AP-induced cerebellar ataxia.