The extracellular signal-regulated kinase 1/2 pathway in neurological diseases: A potential therapeutic target (Review)

Abstract

Abstract. Signaling pathways are critical modulators of a variety of physiological and pathological processes, and the abnormal activation of some signaling pathways can contribute to disease progression in various conditions. As a result, signaling pathways have emerged as an important tool through which the occurrence and development of diseases can be studied, which may then lead to the development of novel drugs. Accumulating evidence supports a key role for extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in the embryonic development of the central nervous system (CNS) and in the regulation of adult brain function. ERK1/2, one of the most well characterized members of the mitogen-activated protein kinase family, regulates a range of processes, from metabolism, motility and inflammation, to cell death and survival. In the nervous system, ERK1/2 regulates synaptic plasticity, brain development and repair as well as memory formation. ERK1/2 is also a potent effector of neuronal death and neuroinflammation in many CNS diseases. This review summarizes recent findings in neurobiological ERK1/2 research, with a special emphasis on findings that clarify our understanding of the processes that regulate the plethora of isoform-specific ERK functions under physiological and pathological conditions. Finally, we suggest some potential therapeutic strategies associated with agents acting on the ERK1/2 signaling to prevent or treat neurological diseases.

The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17β‐oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway

“…These findings are in close agreement with those previously reported by ourselves under normoglycaemic conditions, as well as those reported by Wakade et al showing that p‐ERK1/2 was elevated significantly after MCAO, and also that the SERM tamoxifen attenuated such an effect and correlated with a reduced infarct size. Moreover, inhibitors of ERK1/2 (U0126 and PD184161) have been shown to decrease infarct volume in the MCAO model, as summarised by Sun and Nan . The results of the present study are in line and lend support to the view that therapies targeted at suppression of the ERK1/2 pathway may be beneficial in stroke.…”

Evaluation of neuropathological effects of a high-fat high-sucrose diet in middle-aged male C57BL6/J mice

“…For example, ERK is one of the kinases known to phosphorylate tau and has been shown to be associated with neurofibrillary tangles and senile plaques (Ferrer et al 2001b). Furthermore, abnormal ERK activation in the hippocampus may impair hippocampal function and contribute to memory deficits in AD patients (Sun and Nan 2017). Our results add to the current literature by providing novel insights into the temporal relationship of these kinases to one another in response to a HFS diet.…”

“…). Furthermore, abnormal ERK activation in the hippocampus may impair hippocampal function and contribute to memory deficits in AD patients (Sun and Nan ). Our results add to the current literature by providing novel insights into the temporal relationship of these kinases to one another in response to a HFS diet.…”

The Alzheimer’s disease-associated protectivePlcγ2-P522R variant promotes beneficial microglial functions

“…Itpr1 encodes an Ip3 receptor and acts directly downstream of Plcγ2. Similarly, Mapk/Erk-signaling is induced by Plcγ2 activation [6] and regulates pathways related to survival, proliferation, differentiation, and inflammatory responses in brain immune cells and other cell types [23]. Rac1 and RhoA can be activated in a Plcγ2 and/or Mapk/Erk-dependent manner [24-25] and play pivotal roles in microglia activation, migration, phagocytosis, and neuronal loss [27-29].…”