br Other pathways involved in the preventive and therapeutic
Other pathways involved in the preventive and therapeutic potential of flavonoids in neurodegenerative diseases Rather than the induction of MAPK/ERK pathway, flavonoids actively modulate other critical intracellular neuronal survival and death protein kinases pathways, more importantly PI3K/Akt, protein kinase C (PKC), tyrosine kinase, and the cell death pathways p38 and JNK. In addition, flavonoids also modulate various gene expressions through the activation/inactivation of different transcription factors (Corcoran et al., 2012; Mansuri et al., 2014). Activation of ERK and Akt are generally assumed to be pro-survival, although the inhibition of JNK and p38 functions considered to be neuroprotective (Spencer, 2010). The PI3K/Akt and PKC pathways are pivotal in neuronal survival, specifically through the induction of several pro-survival or anti-apoptotic genes, also via the inhibition of pro-apoptotic proteins. In a chain of events interconnected, the PI3K activation phosphorylates and upregulates the Akt. In consequent, Akt executes a number of downstream effects including prevention of apoptosis mainly through the entospletinib and inactivation of the important pro-apoptotic B-cell lymphoma 2 (Bcl-2) family members (Yao et al., 2012) and the members of caspase family, thus promotes cell survival (Corcoran et al., 2012; Mansuri et al., 2014; Spencer, 2007). A number of flavonoids such as myricetin (Zheng et al., 2012), kaempferol (Park et al., 2011), EGCG (Mandel et al., 2004) and hesperetin (Vauzour et al., 2007) were reported to activate the PI3K/Akt pathway. The activation/inhibition of PKCs leads to the neuroprotection/neuronal death. For instance, the neuroprotective effect of EGCG has been partially implicated to the PKC activation (Williams et al., 2004; Zhao et al., 2017). Stress activated JNK and p38 pathways have also been linked to the preventive and therapeutic potentials of different flavonoids. Furthermore, such cascades have determinative connections to the transcription dependent apoptotic signaling that cause neuronal death, mainly by activating the c-Jun and other AP-1 proteins (Mansuri et al., 2014). It was known long time ago that ERK and JNK act opposite, in particular in the process of neuronal apoptosis (Xia et al., 1995). A great number of studies were conducted to show that flavonoids are capable to interfere neuro-inflammatory pathways by modulating of proinflammatory mediators such as NO, TNF-α, IL-1β, iNOS and cyclooxygenase-2 expression, NADPH oxidase activation, as well as ROS production (Costa et al., 2016; Mansuri et al., 2014; Spagnuolo et al., 2017).
Conclusion remarks: MAPK/ERK and flavonoids: future pharmacological target Currently, there are remarkable interests towards the beneficial effects of natural flavonoids to improve neural performance and to prevent the onset and development of the predominant neurodegenerative diseases; AD, HD and PD. Herbal based natural products, have gained a great deal of attention due to their safe and non-toxic statues. Scientists believe that oxidative stress stimulates a variety of signaling pathways associated with neurodegenerative diseases. Delve deep into the intracellular mechanisms underlying neurodegenerative diseases is mandatory in order to find future pharmacotherapeutics. Mounting evidence suggested that the neuroprotective function of bioflavonoids is mediated by various neuropharmacological effects, including antioxidative stress, their potential to protect the brain against neurotoxins-induced injury and the inhibition of neuroinflammation (Vauzour et al., 2008; Williams and Spencer, 2012). The multiplicity of neuropharmacological activities is found to be supported by the processes that modulate crucial intracellular signaling pathways in CNS, which can result in the prevention of ROS induced neural cell death and the promotion of neuronal survival and proliferation. In fact, natural flavonoids possess selective effects on some specific protein kinases and lipid kinases of the neural signaling pathways including MAPK/ERK and PI3K/Akt pathways. These pathways are typically activated by neurotrophic or growth factors, enable to phosphorylate a multifaceted signaling cascade and stimulate the MEK/ERK. As these biologic factors are proteins, thus their clinical applications face various restrictions in terms of undesirable pharmacokinetics and defects in their delivery to the brain. To solve such problems, an alternative strategy is to find some small substances that can be substituted with these biologic factors of the ERK/MAPK signaling. Natural flavonoids are also applicable to target the proteostasis, which is the quality control machinery of the assembly, structure and function of the cellular protein at genomic, expression and functional levels via different mechanisms. The presence of one or more phenolic group(s) is mainly credited for the neuroprotective effects of polyphenolic phytochemicals (Albarracin et al., 2012; Moosmann and Behl, 1999). Focused research is required to develop novel synthetic flavonoids, by developing drug design and molecular alterations to overcome the existing limitations such as low BBB permeability (Hajieva, 2017). Of note, since ERK has been implicated in cell survival and in some particular conditions induces cell death, in designing experiments and studies cautious should be exercised.Moreover, the hyper-activation of ERK pathway may promote oncogenic transformation.