Br J Pharmacol. 2015 Oct;172(19):4741-56. doi: 10.1111/bph.13248.

Activating mitochondrial function and haemoglobin expression with EH-201, an inducer of erythropoietin in neuronal cells, reverses memory impairment.

 

Horng LY1,2, Hsu PL2, Chen LW1, Tseng WZ1, Hsu KT1, Wu CL2, Wu RT1,2,3.
  • 1Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
  • 2Research Center for Drug Discovery, National Yang-Ming University, Taipei, Taiwan.
  • 3Research Center for Natural Products and Drug Development, Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan.

 

Abstract

BACKGROUND AND PURPOSE:

Memory impairment can be progressive in neurodegenerative diseases, and physiological ageing or brain injury, mitochondrial dysfunction and oxidative stress are critical components of these issues. An early clinical study has demonstrated cognitive improvement during erythropoietin treatment in patients with chronic renal failure. As erythropoietin cannot freely cross the blood-brain barrier, we tested EH-201 (2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside, also known as TSG), a low MW inducer of erythropoietin, for its therapeutic effects on memory impairment in models of neurodegenerative diseases, physiological ageing or brain injury.

EXPERIMENTAL APPROACH:

The effects of EH-201 were investigated in astrocytes and PC12 neuronal-like cells. In vivo, we used sleep-deprived (SD) mice as a stress model, amyloid-β (Aβ)-injected mice as a physiological ageing model and kainic acid (KA)-injected mice as a brain damage model to assess the therapeutic effects of EH-201.

KEY RESULTS:

EH-201 induced expression of erythropoietin, PPAR-γ coactivator 1α (PGC-1α) and haemoglobin in astrocytes and PC12 neuronal-like cells. In vivo, EH-201 treatment restored memory impairment, as assessed by the passive avoidance test, in SD, Aβ and KA mouse models. In the hippocampus of mice given EH-201 in their diet, levels of erythropoietin, PGC-1α and haemoglobin were increased

CONCLUSIONS AND IMPLICATIONS:

The induction of endogenous erythropoietin in neuronal cells by inducers such as EH-201 might be a therapeutic strategy for memory impairment in neurodegenerative disease, physiological ageing or traumatic brain injury.

PMID: 26177968

 

Supplements:

Both EPO and the EPO receptor are expressed in neurons and astrocytes, and EPO is produced primarily by astrocytes in the brain (Juul et al.,1999). Recombinant human EPO (rhEPO) is widely used to enhance erythropoiesis in patients with anaemia and has been found to have many non-hematopoietic beneficial effects, including cardioprotection (Parsa et al., 2003) and neuroprotection (Digicaylioglu and Lipton, 2001). An early clinical study has demonstrated cognitive improvement during EPO treatment among patients with chronic renal failure (Pickett et al., 1999). Recently, studies have shown that high-dose EPO treatments improve hippocampal plasticity and cognitive performance in patients suffering from neuropsychiatric diseases (Ehrenreich et al., 2007). However, rhEPO, given in low doses to treat anaemia or in high doses for tissue protection, increased mortality (Lund et al., 2014).

In the earlier study, we showed EH-201, a pure small molecular compound isolated from a famous anti-aging herb, to be a potent inducer of EPO in non-haematopoietic cells. Also EH-201 showed a therapeutic effect at the dose of 30 mg/kg and 90mg/kg after cisplatin-induced nephropathy or doxorubicin-induced cardiomyopathy was established in mice (Hsu et al., 2013). In the present study, we used EH-201 to induce EPO in neuronal cells and found EPO-mediated activation of mitochondrial function through PPAR-γ coactivator 1α (PGC-1α) and haemoglobin-β expression in these cells. We also were able to show, in vivo, recovery of memory impairment in sleep deprivation, Aβ and kainic Acid mouse models after treatment with dietary EH-201. Therefore, our results suggest that the induction of EPO in neuronal cells might be a therapeutic strategy for memory impairment in neurodegenerative diseases or physiological ageing.

The genotoxicity of EH-201 is safe in the dose of 5g/Kg, and 90 days repeated toxicology also without significant side effect in the dose of 2.5g/Kg. After the ongoing safety pharmacology to been done, EH-201 will entered into clinical trials for several indications in Taiwan first. Our preclinical studies evaluating EH-201 with the unique mechanism that can potentially address aging-related diseases are very interesting and relevant because of the large unmet medical need. EH-201 analogues are also ongoing by computation and chemical synthesis studies. Worldwide patents of EH-201 were granted or in continue application, and its analogues are also submitted for worldwide material patent application.

 

Reference:

Hsu PL, Horng LY, Peng KY, Wu CL, Sung HC, Wu RT (2013). Activation of mitochondrial function and Hb expression in non-haematopoietic cells by an EPO inducer ameliorates ischaemic diseases in mice. Br J Pharmacol 169: 1461–1476.

 

Professor Rong-Tsun WuContact: Rong-Tsun Wu, Ph.D.

Director, Research Center for Drug Discovery

Professor, Institute of Biopharmaceutical Sciences

National Yang-Ming University, Taipei, ROC(Taiwan)

Adjunct professor, Institute of Natural Products

Director, Research Center for Natural Products and Drug Development

Kaohsiung Medical University, Kaohsiung, ROC(Taiwan)

E-mail: rtwu@ym.edu.tw

 

 

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