Caffeic acid phenethyl ester protects nigral dopaminergic neurons via dual mechanisms involving haem oxygenase‐1 and brain‐derived neurotrophic factor

Abstract

BACKGROUND AND PURPOSECaffeic acid phenethyl ester (CAPE) is a component of honey bee propolis that can induce expression of haem oxygenase-1 (HO-1). Because HO-1 induction has been suggested to protect dopaminergic neurons in the substantia nigra, we examined the effect of CAPE in experimental models of dopaminergic neurodegeneration. EXPERIMENTAL APPROACHNeuroprotective effect of CAPE was investigated in rat organotypic midbrain slice cultures and in vivo, using a mouse model of dopaminergic neurodegeneration induced by intranigral injection of LPS and intrastriatal injection of 6-hydroxydopamine. KEY RESULTSCAPE protected dopaminergic neurons in slice cultures from IFN-g/LPS-induced injury. The effect of CAPE was inhibited by zinc protoporphyrin IX, an HO-1 inhibitor, and by neutralizing antibody against brain-derived neurotrophic factor (BDNF). A p38 MAPK inhibitor SB203580 prevented activation of NF-E2-related factor 2, attenuated increased expression of HO-1 and BDNF, and blocked the neuroprotective actions of CAPE. In the LPS-injected mouse model, daily intraperitoneal administration of CAPE protected dopaminergic neurons, up-regulated HO-1 and BDNF, and reduced the increase of activated microglia/ macrophages. Neuroprotective effects of CAPE against LPS-induced injury was prevented by zinc protoporphyrin IX or anti-BDNF antibody. CAPE protected dopaminergic neurons and alleviated methamphetamine-induced rotational behaviour also in 6-hydroxydopamine hemiparkinsonian mice. CONCLUSION AND IMPLICATIONSCAPE is a novel type of neuroprotective agent whose actions are mediated by both HO-1 and BDNF. These findings may provide novel clues to develop neuroprotective agents for treatment of neurodegenerative disorders. Abbreviations6-OHDA, 6-hydroxydopamine; BDNF, brain-derived neurotrophic factor; CAPE, caffeic acid phenethyl ester; GCL, glutamate cysteine ligase; GCLC, catalytic subunit of GCL; GCLM, modifier subunit of GCL; GFAP, glial fibrillary acidic protein; HO, haem oxygenase; iNOS, inducible isoform of nitric oxide synthase; MPP + , 1-methyl-4-phenylpyridinium; Nrf2, NF-E2-related factor 2; SNpc, substantia nigra pars compacta; ZnPPIX, zinc protoporphyrin IX

Caffeic acid phenethyl ester (CAPE) protects PC12 cells from MPP+ toxicity by inducing the expression of neuron-typical proteins

“…These proteins have been associated with differentiation and neurite outgrowth in PC12 cells (Das et al, 2004) and up-regulation of them have been found in PC12 cells stimulated with NGF (Romano et al, 1987;Van Hooff et al, 1986). Therefore, our study is in line with previous studies which demonstrated (i) that CAPE protects nigral dopaminergic neurons via induction of brain-derived neurotrophic factor (BDNF) (Kurauchi et al, 2012) and (ii) induces the expression of NGF and p75 neurotrophin receptor (p75 NTR ) in C6 glioma cells (Lin et al, 2010b). NGF binding to p75 NTR has been associated with both neuronal survival and death, and the balance of these opposing effects is important in the development, maintenance and regeneration of the nervous system (Yamashita et al, 2005).…”

Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress

“…Antioxidants such as resveratrol, caffeic acid, epicatechin ECGC can activate hormetic pathways in neurons and mediate cytoprotection by activating anti-apoptotic proteins (Chen et al, 2005; Kurauchi et al, 2012; Mandel et al, 2008; Ren et al, 2011; Schroeter et al, 2007). For instance, a redox-sensitive transcription factor NF-E2-related factor-2 (Nrf2) is released from the cytosolic repressor protein Keap1 (Kelch ECH associating protein) under oxidative stress, translocates to the nucleus and binds to the antioxidant-response element (ARE), thus activating antioxidant defense enzymes, including glutathione S-transferase, glutathione peroxidase (GPx) and heme oxygenase-1 (HO-1) (Lee and Johnson, 2004).…”

Synthesis of Caffeic Acid Phenethyl Ester Derivatives, and Their Cytoprotective and Neuritogenic Activities in PC12 Cells

“…mp 153−155°C; IR (KBr) ν max 3488, 3346, 1649, 1602, 1551, 1326, 1287, 1189 cm −1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.34 (1H, d, J = 16.0 Hz, H-β), 7.13−7.24 (5H, m, H-2′, 3′, 4′, 5′, 6′), 6.93 (1H, d, J = 1.6 Hz, H-2), 6.82 (1H, dd, J = 1.6, 8.4 Hz, H-6), 6.71 (1H, d, J = 8.4 Hz, H-5), 6.16 (1H, d, J = 16.0 Hz, H-α), 3.48 (2H, t, J = 7.2 Hz, H-α′), 2.78 (2H, t, J = 7.2 Hz, H-β′); HRESIMS [M − H] − m/z 282.1125 (Calcd for C 17 H 16 NO 3 , 282.1130).Caffeic Acid 4-Hydroxyphenylacetamide(17). The title compound was prepared according to method C as light yellow powder (35 mg, 11.7% yield).mp 211−212°C; IR (KBr) ν max 3369, 1646, 1604, 1516, 1241 cm −1 ; 1 H NMR (400 MHz, CD 3 OD) δ 7.37 (1H, d, J = 15.6 Hz, H-β), 7.05 (2H, d, J = 8.4 Hz, H-2′, 6′), 6.99 (1H, d, J = 2.0 Hz, H-2), 6.89 (1H, dd, J = 2.0, 8.4 Hz, H-6), 6.75 (1H, d, J = 8.4 Hz, H-5), 6.70 (2H, d, J = 8.4 Hz, H-3′, 5′), 6.33 (1H, d, J = 15.MHz, CD 3 OD) δ 7.52 (1H, d, J = 16.0 Hz, H-β), 7.03 (1H, d, J = 2.0 Hz, H-2), 6.94 (1H, dd, J = 2.0, 8.0 Hz, H-6), 6.78 (1H, d, J = 8.0 Hz, H-5), 6.70 (1H, d, J = 2.0 Hz, H-2′), 6.70 (1H, d, J = 8.0 Hz, H-5′), 6.58 (1H, dd, J = 2.0, 8.0 Hz, H-6′), 4.29 (2H, t, J = 7.2 Hz, H-α′), 2.84 (2H, t, J = 7.2 Hz, H-β′); HRESIMS [M − H] − m/z 315.0862 (Calcd for C 17 H 15 O 6 , 315.0869).…”