investigated the beneficial effect of RUF regarding hippocampal neurogenesis in their latest research [30]. Treatment with 3mg/kg RUF for 4 weeks in aged gerbils led to considerable increase in neurogenesis, newborn cell proliferation and maturation, with memory and learning abilities simultaneously improved. Finally, elevated levels of IGF-1, its receptor IGF-1R and CREB phosphorylation after RUF treatment together accounted for the mechanism of RUF. It is concluded that RUF improved neurogenesis in the hippocampus through stimulating IGF-1 signaling pathways [30].
Nevertheless, the dualistic nature of IGF-1 is a big challenge of applying IGF-1 treatment to clinical trails [31]. Recent studies proposed that in humans, optimal cognitive functioning required an optimum level of IGF-1 and both low and high levels of IGF-1 may impair cognition [32, 33]. Chigogora et al. discovered that both low and high levels of IGF-1 might be association with higher risk of depression in humans [33]. Moreover, a recent report proposed pro-epileptic effect of IGF-1 and showed that long-term IGF-1 exacerbated epileptogenesis in vitro after brain injury [31]. Further researches are needed to determine the optimum dose of IGF-1 required in human.
The effect of IGF-1 on hippocampal neurogenesis is known to rely on the activation of diverse intracellular regulatory cascades, including ERK and PI3K, following IGF-1 binding to IGF-1R [34]. Besides, overexpression of IGF-1 in aged mice also significantly increased the phosphorylation level of Ca2+- calmodulin-dependent kinase II (CaMKII) [26], a downstream protein of PLCγ pathway [12]. Taken together these studies indicate that IGF-1 exerts regulatory control over hippocampal neurogenesis sharing similar signals (PLCγ, PI3K and ERK) with BDNF pathways (Figure 1).
Exercise increases neurogenesis via combined effects of BDNF and IGF-1
Physical exercise has always been one of the most promising methods aimed at brain wellbeing improvement, due to its distinct neuroprotective benefits. It has been illustrated that running rescues brain functions by boosting the expression levels of neurotrophic factors, including BDNF and IGF-1 [35,36]. Significantly, depletion of BDNF or IGF-1 through their specific antagonist eliminated exercise-induced improvements in cognition and hippocampus [36-38], showing that BDNF and IGF-1