Redox modulation of cellular stress response and lipoxin A4 expression by Hericium Erinaceus in rat brain: relevance to Alzheimer's disease pathogenesis

Abstract

Background: There has been a recent upsurge of interest in complementary medicine, especially dietary supplements and foods functional in delaying the onset of age-associated neurodegenerative diseases. Mushrooms have long been used in traditional medicine for thousands of years, being now increasingly recognized as antitumor, antioxidant, antiviral, antibacterial and hepatoprotective agent also capable to stimulate host immune responses.

Results: Here we provide evidence of neuroprotective action of Hericium Herinaceus when administered orally to rat. Expression of Lipoxin A4 (LXA4) was measured in different brain regions after oral administration of a biomass Hericium preparation, given for 3 month. LXA4 up-regulation was associated with an increased content of redox sensitive proteins involved in cellular stress response, such as Hsp72, Heme oxygenase -1 and Thioredoxin. In the brain of rats receiving Hericium, maximum induction of LXA4 was observed in cortex, and hippocampus followed by substantia Nigra, striatum and cerebellum. Increasing evidence supports the notion that oxidative stress-driven neuroinflammation is a fundamental cause in neurodegenerative diseases. As prominent intracellular redox system involved in neuroprotection, the vitagene system is emerging as a neurohormetic potential target for novel cytoprotective interventions. Vitagenes encode for cytoprotective heat shock proteins 70, heme oxygenase-1, thioredoxin and Lipoxin A4. Emerging interest is now focussing on molecules capable of activating the vitagene system as novel therapeutic target to minimize deleterious consequences associated with free radical-induced cell damage, such as in neurodegeneration. LXA4 is an emerging endogenous eicosanoid able to promote resolution of inflammation, acting as an endogenous "braking signal" in the inflammatory process. In addition, Hsp system is emerging as key pathway for modulation to prevent neuronal dysfunction, caused by protein misfolding.

Conclusions: Conceivably, activation of LXA4 signaling and modulation of stress responsive vitagene proteins could serve as a potential therapeutic target for AD-related inflammation and neurodegenerative damage.

Keywords: Alzheimer’s disease; Heat shock protein70; Heme Oxygenase-1; Lipoxin A4; Nutritional mushrooms.

Fig. 1

Regional distribution of Lipoxin A4 in rat brain. LXA4 protein levels in different brain regions and in total brain of control or H. erinaceus-fed rats. Values are expressed as mean ± SEM of three independent analyses on 10 animals per group. CX: cortex; Hp: Hippocampus; Cb: cerebellum; TB: Total Brain. H. erinaceus, given orally at the dose of 200 mg/Kg for 3 month. *P < 0.05 vs control

Fig. 2

a Lipoxin A4 in rat blood. LXA4 levels in plasma and in lymphocytes from rats fed H. erinaceus biomass preparation as compared to control group. Data are expressed as mean ± SEM of 10 animals per group. *P < 0.05 vs controls. b Lipoxin A4 in Liver and Kidney. LXA4 levels in liver and kidney from rats fed H. erinaceus biomass preparation as compared to control group. Data are expressed as mean ± SEM of 10 animals per group. *P < 0.05 vs controls

Fig. 3

a Inducible heme oxygenase in Total Brain. HO-1 protein levels in the brain of rats fed H. erinaceus biomass preparation as compared to control group. Total brain homogenates from control and mushroom supplemented rats were assayed for HO-1 expression by Western blot. The bar graph shows densitometric values, expressed as mean standard error of mean of 3 independent analyses. P < 0.05 vs control. In the representative immunoblot shown, β-actin has been used as loading control. D.U., densitometric units. b Inducible Heat shock protein 70 in Total brain. Hsp70 protein levels in the brain of rats fed H. erinaceus biomass preparation as compared to control group. Total brain homogenates from control and mushroom supplemented rats were assayed for Hsp70 expression by Western blot. The bar graph shows densitometric values, expressed as mean standard error of mean of 3 independent analyses. P < 0.05 vs control. In the representative immunoblot shown, β-actin has been used as loading control. D.U., densitometric units. c Thioredoxin in Total brain. Trx protein levels in the brain of rats fed H. erinaceus biomass preparation as compared to control group. Total brain homogenates from control and mushroom supplemented rats were assayed for Trx expression by Western blot. The bar graph shows densitometric values, expressed as mean standard error of mean of 3 independent analyses. P < 0.05 vs control. In the representative immunoblot shown, β-actin has been used as loading control. D.U., densitometric units

Fig. 4

a Regional distribution of HO-1 in rat brain. HO-1 protein levels in different brain regions of rats fed H. erinaceus biomass preparation as compared to control group. Brain region homogenates from control and mushroom supplemented rats were assayed for HO-1 expression by Western blot. The bar graph shows densitometric values, expressed as mean standard error of mean of 3 independent analyses. P < 0.05 vs control. In the representative immunoblot shown, β-actin has been used as loading control. D.U., densitometric units. CX: cortex; Hp: Hippocampus; Cb: cerebellum. b Regional distribution of Hsp70 in rat brain. Inducible Hsp70 protein levels in different brain regions of rats fed H. erinaceus biomass preparation as compared to control group. Brain region homogenates from control and mushroom supplemented rats were assayed for Hsp70 expression by Western blot. The bar graph shows densitometric values, expressed as mean standard error of mean of 3 independent analyses. P < 0.05 vs control. In the representative immunoblot shown, β-actin has been used as loading control. D.U., densitometric units. CX: cortex; Hp: Hippocampus; Cb: cerebellum. c Regional distribution of thioredoxin in rat brain. Trx protein levels in different brain regions of rats fed H. erinaceus biomass preparation as compared to control group. Brain region homogenates from control and mushroom supplemented rats were assayed for Trx expression by Western blot. The bar graph shows densitometric values, expressed as mean standard error of mean of 3 independent analyses. P < 0.05 vs control. In the representative immunoblot shown, β-actin has been used as loading control. D.U., densitometric units. CX: cortex; Hp: Hippocampus; Cb: cerebellum

Fig. 5

a Inducible heme oxygenase-1 in peripheral tissues. HO-1 protein levels in liver, lymphocyte, kidney and plasma from rats fed H. erinaceus biomass preparation as compared to control group. Samples from control and mushroom supplemented rats were assayed for HO-1 expression by Western blot. Bar graph shows the values expressed as mean standard error of mean of 3 independent analyses. P < 0.05 vs control. In the representative immunoblot shown, β-actin has been used as loading control. D.U., densitometric units. b. Inducible heat shock protein 70 in peripheral tissues. Inducible Hsp 70 protein levels in liver, lymphocyte, kidney and plasma from rats fed H. erinaceus biomass preparation as compared to control group. Samples from control and mushroom supplemented rats were assayed for Hsp70 expression by Western blot. Bar graph shows the values expressed as mean standard error of mean of 3 independent analyses. P < 0.05 vs control. In the representative immunoblot shown, β-actin has been used as loading control. D.U., densitometric units

Fig. 6

Inducible Thioredoxin in peripheral tissues. Trx protein levels in lymphocyte from rats fed H. erinaceus biomass preparation as compared to control group. Samples from control and mushroom supplemented rats were assayed for Trx expression by Western blot. Bar graph shows values expressed as mean standard error of mean of 3 independent analyses. P < 0.05 vs control. The representative immunoblot shows Trx and β-actin, which has been used as loading control. D.U., densitometric units