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

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-ß-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-ß (Aß)-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, Aß 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.

Internal ribosome entry site of bFGF is the target of thalidomide for IMiDs development in multiple myeloma.

Although new analogues of immunomodulatory drugs (IMiDs) are being developed for MM, the molecular mechanism of these drugs remains unclear. In the current study, we used MM cell lines as a model to investigate the molecular mechanism of thalidomide and to compare its potency with IMiDs such as pomalidomide. We determined that thalidomide did not inhibit cell proliferation of RPMI8226 and U266 MM cells, whereas pomalidomide showed a significant inhibitory effect on these two MM cell lines. Interestingly, we further demonstrated that although thalidomide down-regulated bFGF translation through the inhibition of IRES even at 0.1 µg/ml, pomalidomide did not have a similar affect bFGF levels. A colony formation assay demonstrated that thalidomide and the bFGF knock-down clones caused a significant reduction in the clonogenic ability of MM cells, and treatment with exogenous bFGF can recover the clonogenic ability of thalidomide-treated cells and knock-down clones, but not that of pomalidomide-treated cells. This implies that thalidomide, but not pomalidomide, targets the IRES of FGF-2. In conclusion, our results highlight a non-cytotoxic anticancer drug target for thalidomide, the IRES of bFGF, and provide the mechanistic rationale for developing IMiDs as anti-cancer therapeutics in MM patients, with improved potency and fewer side effects.

Activating mitochondrial regulator PGC-1α expression by astrocytic NGF is a therapeutic strategy for Huntington's disease.

Mitochondrial dysfunction plays an important role in Huntington's disease (HD). NGF gene delivery in AD patients showed an increase in brain energy metabolism and NGF has been shown neuroprotective effects against mitochondrial toxins. However, the role of NGF in regulating mitochondrial function is unclear. Here, we found that NGF-stimulated mitochondrial biogenesis in PC12 and primary neuron cells. Our results demonstrated that peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) is a downstream key target of the NGF signalling pathway. In a 3-nitropropionic acid (3-NP) cell model, NGF treatment rescued the defects in mitochondrial activity and mitochondrial membrane potential. Since NGF cannot freely cross blood-brain barrier, we found an astrocytic NGF inducer, Ganoderma lucidum (GaLu) extract. Its active constituents had potent effects on the induction of NGF in primary astrocytes. Among the identified ingredients, ganoderic acid C2 was most effective. We further found that GaLu-conditioned media can enhance mitochondrial biogenesis in PC12 cells and preventing NGF signalling using NGF antibody or PGC-1α siRNA blocked these effects. Moreover, GaLu and ganoderic acid C2-conditioned media treatment attenuated mitochondrial defects in 3-NP cell model. After 3-NP-induced behavioural impairment and striatal degeneration in mice, GaLu treatment therapeutically restored the behaviour score, sensorimotor ability and neuronal loss. We found that striatal NGF, PGC-1α expression level and succinate dehydrogenase activity were recovered in GaLu-fed mice. These results suggest that the NGF-signalling pathway connected to the mitochondrial regulator, PGC-1α, expression. This signalling triggered by astrocytic NGF with small molecule inducers may offer a therapeutic strategy for HD.

Induction of differentiation in rat C6 glioma cells with Saikosaponins.

The effects of saikosaponins (a, b(1), b(2), c, d), isolated from Bupleurum Radix, on the induction of differentiation in rat C6 glioma cells were studied. Saikosaponins a and d were shown to inhibit cell proliferation and alter cell morphology. In addition to cytostasis, the enzymatic activities of glutamine synthetase (GS) and 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) were also noticeably increased after treatment with saikosaponin a. Nevertheless, saikosaponin d only showed an increase of GS activity, no significant changes in CNP activity were found. These results suggest that saikosaponin a can induce the differentiation of C6 glioma cells into astrocytes and/or oligodendrocytes, but saikosaponin d can only induce the differentiation of C6 glioma cells into astrocytes.