Fos Protein as a Marker of Neuronal Activity: a Useful Tool in the Study of the Mechanism of Action of Natural Products with Analgesic Activity

Abstract

Pain treatment is still ineffective in many conditions and remains one of the greatest challenges of modern medicine. Historically, due to the incredible variety of pharmacologically promising natural products (NPs) and the chemical complexity of their compounds, scientists have explored their use as a source of treatment for diseases or symptomatology. Fos protein and its precursor, the gene c-Fos, have been the subject of study in relation to the pathophysiology of pain as a possible tool to aid in its understanding. More recently, it has become a useful tool in the study of NPs with analgesic profile. Thus, this systematic review aimed to investigate the analgesic effect of NPs and derivatives through changes in Fos protein or c-Fos expression in nervous system central. The search terms "analgesics," "Fos," and "drug effects" were used in the databases PubMed, MEDLINE, Scopus, and Embase. Forty-six articles were identified. Twenty-five articles investigated Fos expression in the spinal cord, 1 in dorsal root ganglion, 11 in brain areas, and 9 investigated the association between the spinal cord and brain areas. Although Fos protein expression has been used as a tool in the studies of the mechanism of action of pain in relation to NPs with analgesic activity, the associations between brain areas and the spinal cord-and the possible pathways involved-have not yet been fully elucidated and deserve further study.

Terpenes as possible drugs for the mitigation of arthritic symptoms – A systematic review

“…Kang et al (2008) demonstrated that oral administration of ursolic acid, a natural pentacyclic triterpenoid carboxylic acid, decreased the number of c-FOS positive neurons in the lumbar spinal cord, causing the inhibition of arthritic nociceptive input to the spinal cord. This finding is in agreement with other studies that reported that terpenes have effective action in inhibiting c-FOS protein expression; and it is also associated with the antinociceptive effect of this molecule (Quintans-Júnior et al, 2016, Santos et al, 2017. Ma and Jiang (Ma and Jiang, 2016), proposed that terpenes are among the most effective compound groups for the treatment of rheumatoid arthritis in traditional Chinese medicine.…”

“…Moreover, the synthesis and secretion of MMP are trigged by increased c-FOS expression, which provokes arthritic joint destruction (Aikawa et al, 2008, Cheung, 2006, Chu et al, 2004, McCarthy et al, 1998. c-FOS protein is routinely used as an indicator for neuronal activation and is expressed in different conditions, including in inflammatory and pain conditions (Santos et al, 2017). Studies have reported that rheumatoid arthritis and osteoarthritis patients present up-regulated c-FOS protein expression in the synovial tissue (Cheung, 2006, McCarthy et al, 1998, Trabandt et al, 1992.…”

“…Features characteristic of joint destruction in rheumatic diseases, including synovial overgrowth and bone resorption, are experimentally produced by augmenting c-fos gene expression and its protein products, c-fos (Shiozawa et al, 1997). Several studies indicate that terpenes are able to suppress c-FOS expression in inflammatory and non-inflammatory diseases (Nascimento et al, 2014, Santos et al, 2017. Lee et al (2013) reported that the sesquiterpene lemnalol decreased c-FOS expression in the ankle synovium of MSU induced arthritis rats.…”

A Review of Spinal and Peripheral Neuromodulation and Neuroinflammation: Lessons Learned Thus Far and Future Prospects of Biotype Development

“…Fos protein, a marker and research tool for neuronal activation following painful stimuli, is expressed in multiple areas of spinal laminae in response to peripheral inflammation . EA exerts anti‐nociceptive effects at the level of the spinal cord via inhibition of Fos protein expression and interacts with the neural transmission of analgesia via glutamate, cytokines, signal molecules, and norepinephrine .…”

Nod-like receptors are critical for gut-brain axis signaling

“…Neural activation is critical for memory formation with acute stress-induced increases in glucocorticoids necessary for hippocampal neuronal survival, memory acquisition, and consolidation (26). To identify the neural circuitry underlying the differential stress susceptibility between NodDKO(+WAS) and WT(+WAS) mice, we measured expression of the immediate early genes (IEGs) Arc and c-Fos, indicative of neural activation (27, 28). Arc mRNA expression was significantly increased in the hippocampus of WT(+WAS) but not NodDKO(+WAS) mice compared with WT(-WAS) or NodDKO(-WAS) mice respectively (Fig 2A).…”