Low-molecular-weight compounds having neurotrophic activity in cultured PC12 cells and neurons

Abstract

Recent reports have indicated that some low-molecular-weight compounds mimic neurotrophic factors inducing neurite outgrowth and neuroprotection. Carnosic acid (CA) promotes neurite outgrowth through the activation of Nrf2 in PC12 cells. CA also protects neurons via the keap/Nrf2 transcriptional pathway from oxidative stress. Forskolin-induced neurite outgrowth is mediated by activation of the PKA signalling pathway and this PKA-mediated neurite outgrowth is achieved by the expression of nur77 in PC12 cells. In addition, forskolin at its low concentration is closely related to the cAMP-induced protective function against L-DOPA-induced cytotoxicity in PC12 cells. A HDAC inhibitor trichostatin A (TSA) increases neurite length via p53 acetylation in rat cultured cerebellar granule neurons and in cerebral cortical neurons, and also protects neurons against glutathione depletion-induced oxidative stress. Recently, it was revealed that Nrf2 and p53 bind to CBP/p300 directly, and Nur77 is acetylated in vivo and in vitro by CBP/p300. Acetylation of Nrf2, p53 and Nur77 by CBP/p300 may constitute a novel similar regulatory mechanism for low-molecular-weight compounds with neurotrophic activities.

Nrf2/ARE-mediated antioxidant actions of pro-electrophilic drugs

“…In all likelihood paracrine or non-cell autonomous effects are the most plausible mechanism for neuroprotection by most PEDs, and candidate mediators of neuroprotection that are released from astrocytes have been identified by microarray analysis [64]. For example, CA potently releases nerve growth factor (NGF) protein from glioblastoma cells and primary astrocytes [75–79]. Release of other non-cell autonomous, potentially neuroprotective molecules may include additional neurotrophins, such as brain-derived neurotrophic factor (BDNF) or ciliary neurotrophic factor (CNTF).…”

“…In neurons, CA induces phosphorylation of Trks and p62/ZIP, both of which positively activate the NGF signaling pathway [75]. Since CA induces expression of both NGF and GSH in primary astrocytes, it is likely that these and other trophic agents are released by the astrocytes to act on contiguous neurons in the brain [77–79]. Therefore, these prior reports suggest that CA can activate non-cell autonomous as well as cell autonomous effects on neurons (Fig.…”

“…Moreover, CA and CS share similar biological actions although CA is more potent than CS in various model systems [42, 43]. It should be noted that CA and CS are capable of both directly scavenging free radicals [40] and indirectly increasing endogenous cellular antioxidant defenses via activation of the Nrf2 transcriptional pathway, as well as potentially via multiple other mechanisms [10, 11, 79, 92–94]. We feel, however, that activation of the Nrf2 pathway represents a major mechanism of action for CA and CS, particularly in the central nervous system (CNS).…”

“…CA is also thought to act directly on neurons to upregulate TrkA, ERK1/2 and p62/ZIP via Nrf2 activation [12, 75, 79]. CA-activated Nrf2 then induces p62/ZIP expression, which plays an important role in mediating neurotrophic actions [12, 75, 79]. …”

Regulating the Ubiquitin/Proteasome Pathway Via cAMP-signaling: Neuroprotective Potential

“…Here we review a few emerging studies focusing on the neuroprotective effects of forskolin. In PC12 cells, forskolin induces neurite outgrowth via Nur77, an orphan nuclear receptor and immediate-early response gene, and protects these cells against L-3,4-dihydroxyphenylalanine (L-DOPA) toxicity (75). Activation of cAMP-PKA signaling by forskolin triggered synaptic vesicle exocytosis and recycling in NT2 cells (76).…”