Securinine Promotes Neuronal Development and Exhibits Antidepressant-like Effects via mTOR Activation

Abstract

Impaired differentiation of newborn neurons or abnormalities at the synapses resulted from stress maladaptation could be the key etiology of depression. Recent studies have shown that mTOR, a crucial factor for neuronal differentiation and synapse development, acts as a common factor that mediates the rapid antidepression effects of several new-class antidepressants. In this study, the antidepressant-like activity of securinine, an alkaloid that has central nervous system stimulation ability, was investigated. Both securinine and its enantiomer virosecurinine exhibited potent in vitro activity on neuronal differentiation and synapse development in Neuro-2a cells and cultured hippocampal neurons, and this activity was dependent on the activation of the AKT-mTOR-S6K pathway. Interestingly, only securinine but not virosecurinine showed mTOR stimulation and antidepressant-like activity in mice. Importantly, a single dose of securinine was capable of alleviating the behavioral deficits induced by both acute and chronic stress models within 30 min of administration, suggesting that securinine has rapid onset of action. Moreover, neither a single dose nor a 3 week treatment of securinine had adverse effects on exploratory locomotion of mice. Together, this study identifies that securinine is a potent agent in promoting neuronal differentiation and synapse formation and shows rapid antidepressant-like activity, without inducing abnormal locomotion, via mTOR activation.

eEF2 in the prefrontal cortex promotes excitatory synaptic transmission and social novelty behavior

“…The depression‐like behavior was tested by a forced‐swim test as previously described (Xiao et al , 2021). Four mice were tested simultaneously in an opaque white compartment (66.7 cm long, 16 cm wide, and 26 cm high), which is equally divided into four parts, each containing a clear Plexiglas cylindrical container.…”

“…Experimenters were blind to the genotypes during testing. More behavioral experiments were performed following our previous protocols (Guo et al, 2021(Guo et al, , 2022Xiao et al, 2021;Yang et al, 2021c), and the detailed procedures are described as follows.…”

“…The ratio of the averaged relative quantitative value of each protein in multiple repeated samples is used as the Fold Change (FC). The top 15% proteins of upregulated or downregulated were selected for heatmap generating and Gene Ontology (GO) annotation illustrated by clusterProfiler R package (Wu et al, 2021). GSEA software v4.1.0 was used to identify the significantly enriched specified GO terms (Mootha et al, 2003;Subramanian et al, 2005), with the number of permutations set at 1,000 and permutation type set as gene_set.…”

Activation of the mTOR pathway promotes neurite growth through upregulation of CD44 expression

“…[16][17][18][19] Several studies have shown that the mTOR signalling pathway plays a crucial role in the formation of nerve synapses, neuronal survival, nerve cell development, and axonal regeneration and extension. [20][21][22] Identifying the underlying molecules associated with the mechanisms downstream of the mTOR pathway and neural regeneration may provide useful therapeutic targets for CNS injury. Studies have shown that CD44 is closely related to axonal development.…”