Carnosic Acid and Mechanisms of Neuroprotection: Comparison
Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by R. M. Damian Holsinger.

Carnosic acid (CA) is a diterpenoid abundantly present in plants belonging to the genus Rosmarinus and Salvia of the family Lamiaceae, accounting for their application in traditional medicine. CA exerts its neuroprotective effects through a diverse range of mechanisms, some of which include the prevention of amyloid-β (Aβ)-induced neurodegeneration, induction of autophagy, alleviation of oxidative stress and via anti-apoptotic effects.

  • neuroprotection
  • carnosic acid
  • natural sources
  • neurodegeneration
  • autophagy
  • oxidative stress

1. Induction of Autophagy

The pathogenesis of most neurodegenerative disorders bears a resemblance to the manner in which the pathogenic proteins are disposed of by neurons and glia. Autophagy, a homeostatic process by which the degradation of long-lived cellular proteins, lipids, and dysfunctional organelles occur within the lysosomal machinery, plays a crucial role in maintaining the metabolic balance between synthesis, degradation, and subsequent turnover of cytoplasmic material [12,13,14][1][2][3]. Since it prevents the buildup of protein aggregates and damaged mitochondria and organelles, loss of autophagy or its dysregulation may lead to atrophy and neuronal death [15][4]. Autophagic dysregulation is also implicated in neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and lysosomal storage disorders (LSDs) [14][3].
A study employing human neuroblastoma SH-SY5Y cells revealed an instrumental role for CA in the reduction of Aβ-induced apoptosis and the accumulation of toxic proteins through the induction of autophagy. Aβ aggregation is a hallmark feature of AD and is a key target of AD-related therapies. The study by Liu and colleagues demonstrated that CA-induced autophagy via AMP-activated protein kinase (AMPK) is an important regulator of cellular metabolism [16][5]. AMPK triggers autophagy to avoid oxidative stress and mitochondrial dysfunction in cells treated with CA, highlighting a therapeutic mechanism of CA against Aβ [16][5]. In vitro studies that investigated the effect of pre-treating SH-SY5Y cells with CA prior to serum starvation revealed that pretreatment significantly protected these cells against nutrient depletion [17][6]. The cytoprotective effects of CA were afforded by the phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (Erk1/2) and moderate activation of autophagy since pretreatment with LY294002 and U-0126, inhibitors of Akt and Erk1/2 phosphorylation, abolished the protective effects [17][6].
Another mechanism by which CA influences autophagy is through the parkin pathway. Parkin is an E3 ubiquitin ligase that catalyzes the conjugation of ubiquitin to abnormal proteins, facilitating their degradation by the ubiquitin proteasome system (UPS) [18][7]. Parkin gene mutations have been implicated in the pathogenesis of neurodegenerative diseases, including Parkinson’s [19,20,21][8][9][10]. CA was shown to prevent cell death via induction of the parkin pathway, enhancing levels of parkin protein, the UPS, and α-synuclein degradation [22][11]. The interaction between parkin and Beclin1 is considered to facilitate autophagosome maturation [23][12]. CA substantially enhances the parkin/Beclin1 interaction, inducing autophagy [24][13]. These effects were attenuated by wortmannin and bafilomycin A1 (an autophagosome-lysosome fusion blocker) [24][13]. Moreover, CA has also been shown to mitigate mitochondrial impairment, which also involves the activation of the PINK1/parkin/mitophagy pathway [25][14]. The neuroprotective effects of CA have also been attributed to the upregulation of OPA1 (OPA1 mitochondrial dynamin-like GTPase) via activation of the parkin/IKKγ/p65 pathway and are associated with an enhancement of mitochondrial biogenesis. This pathway is linked to the inhibition of Parkin-interacting substrate (PARIS) and induction of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α) by parkin [26,27][15][16]. This interaction has been shown to prevent the degeneration of dopaminergic neurons, demonstrating the therapeutic potential of CA against PD [27][16].

2. Alleviation of Oxidative Stress

Oxidative stress is a major contributing factor to neurodegenerative disorders [28][17]. Many studies have highlighted the anti-inflammatory and anti-oxidative properties of CA. Hou and colleagues [29][18] demonstrated the neuroprotective effect of CA on neuronal cells subjected to ischemia/hypoxia injury via the scavenging or reduction of ROS (reactive oxygen species) and NO (nitric oxide) and inhibition of COX-2 and MAPK pathways [29][18]. CA also displayed protective effects against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity by increasing the expression of antioxidant enzymes, including c-glutamate-cysteine ligase catalytic (GCLC) subunit, c-glutamate-cysteine ligase modifier (GCLM) subunit, superoxide dismutase (SOD), and glutathione reductase [30][19]. Furthermore, CA was also demonstrated to be cytoprotective against chlorpyrifos (CPF)-induced inflammation, oxidative stress, and neurotoxicity in brain and eye tissues of mice [31][20] as well as in SH-SY5Y cells [32][21]. CA protects against oxidative stress by employing various mechanisms, among which the induction of Nrf2-ARE and the activation of PI3K/Akt signaling pathways are the most significant and widely studied.

3. Attenuation of Apoptosis

Although many studies highlight the role of CA in modulating autophagy, as discussed earlier, it is also found to play a critical role in the attenuation of apoptosis. Investigations have used variously in vitro and in vivo models of apoptosis to evaluate the neuroprotective role of CA and have revealed regulation at the level of apoptosis-inducible genes [59][22]. Studies in cultured dopaminergic cells (SN4741) employing the organochlorine pesticide dieldrin, which is known to be a risk factor for PD, revealed that neuroprotection afforded by CA was due to the repression of apoptosis-related caspase-3 and -12 and the stress signaling molecule c-Jun N-terminal kinase (JNK) [60][23]. Pretreatment of SN4741 cells with CA also significantly attenuated the downregulation of BDNF, a key molecule associated with dopaminergic neuron survival and maturation [60][23]. Treatment of these cells with dieldrin resulted in a 61% reduction in BDNF release from these cells, whereas pretreatment with 10 μM CA maintained levels of BDNF at basal expression [60][23]. Intriguingly, these results suggest that treatment of SN4741 cells with 10 μM CA results in a 1.5-fold increase in levels of BDNF, suggesting that prophylactic treatment with CA may support dopaminergic and other cells in the brain.
CA was also reported to exert a neuroprotective effect following subarachnoid hemorrhage induced by early brain injury through the inhibition of apoptosis [65][24]. Rats were subjected to a sub-arachnoid hemorrhage procedure, and those in the experimental group were then administered a 3 mg/kg dose of CA intraperitoneally. CA was shown to ameliorate brain edema and blood-brain barrier (BBB) disruption, as well as reduce neuronal death via apoptosis [65][24]. CA was also shown to increase SIRT1, a member of the highly conserved (NAD+)-dependent class of histone deacetylases responsible for combatting ROS and apoptosis, MnSOD (manganese superoxide dismutase, a metalloprotein that prevents mitochondrial dysfunction) and Bcl-2 (the founding member of a family of regulator proteins that regulate cell death) expression [65][24], as well as decreased p66shc, Bax, and cleaved caspase-3 expression. The anti-apoptotic effects of CA were proposed to be facilitated through the SIRT1/p66shc signaling pathway [65,66][24][25].
Importantly, CA was shown to inhibit cell growth and induce apoptosis in IMR-32 human neuroblastoma IMR-32 cells [67][26]. The induction of apoptosis was accompanied by ROS-mediated p38 MAPK activation resulting in a decrease in cell viability [67][26]. Intriguingly, these results suggest that the activity of CA is selective in its regulation of cell viability and apoptosis, whereby these processes are activated by CA to restore physiological states, implying the substantive therapeutic potential of this compound that warrants extensive investigation.

4. Effects of Carnosic Acid in Amyloid-β-Mediated Neurodegeneration

Brain atrophy associated with the deposition of Aβ in extracellular neuritic plaques is the most prominent neuropathological hallmark of Alzheimer’s disease (AD) [68][27]. Aβ-peptide, which constitutes the major component of amyloid plaques, is a 4-kDa peptide formed by the proteolytic cleavage of the amyloid precursor protein (APP) by β-secretase and the γ-secretase complex of proteins [69,70][28][29]. Cleavage of APP by β-secretase (β-site APP-cleaving enzyme-1 (BACE1)) catalyzes the critical step in the generation of Aβ. However, the constitutive pathway of APP processing is via α-secretase cleavage that results in the generation of a soluble ectodomain fragment termed soluble APPα (sAPPα), which possesses neurotrophic and neuroprotective properties [71,72,73][30][31][32]. The protective role of CA against neurodegeneration resulting from the presence of Aβ is well documented. An investigation of the effects of CA on Aβ production in SH-SY5Y human neuroblastoma cells revealed a critical role for this antioxidant in the suppression of Aβ42 generation, an isoform of the peptide that is known to be more hydrophobic and toxic as well as possessing faster oligomerizing properties compared to Aβ40. In the presence of CA, APP cleavage was shuttled to the α-secretase pathway, thereby precluding Aβ generation [74][33]. This shuttling in the presence of CA is driven by the upregulation of tumor necrosis factor-α-converting enzyme (TACE) mRNA, a member of the ADAM (a disintegrin and metalloproteinase) family of proteases, which contributes to α-secretase cleavage of APP [74][33]. Similarly, a substantial reduction in Aβ production by CA via the activation of TACE was evident in U373MG human astrocytoma cells [75][34]. Aβ also interacts with N-methyl-D-aspartate receptors (NMDARs) to induce apoptosis and synaptic dysregulation. In another study on SH-SY5Y cells, CA was shown to inhibit the phosphorylation of the NMDAR subtype 2B (NMDAR2B) receptor, thereby suppressing apoptosis and restoring expression of synaptic proteins including BDNF, postsynaptic density protein-95 (PSD-95), and synaptophysin [76][35]. Additionally, CA significantly attenuated apoptosis induced by Aβ42/43, further highlighting its therapeutic potential against Aβ-induced neurotoxicity [77][36].
In vivo, CA has been demonstrated to be protective to neurons in subfield CA1 (cornu Ammonis) of the hippocampus in an acute experimental rat model of AD (bilateral administration of Aβ into the hippocampus) where Aβ accumulation leads to neurodegeneration of the hippocampus [78][37]. Employing a similar in vivo paradigm, Rasoolijazi and colleagues [79][38] demonstrated the neuroprotective effects of CA on cognitive impairment associated with Aβ-induced neurotoxicity in the rat hippocampus. CA was shown to significantly improve short-term and spatial memory attributes in rat models of AD [79][38]. Furthermore, CA also delayed the deposition of Aβ and protected cells against Aβ-induced cholinergic and mitochondrial dysfunction in a Caenorhabditis elegans model of AD [80][39], thereby reiterating its promising potential as a neuroprotective agent against AD-associated neurodegeneration.
In recent efforts incorporating biomedical advances, nano-carrier packaged CA reduced the deposition of Aβ, subsequently restoring cognitive deficits through the inhibition of the CCAAT-enhancer-binding protein β (CEBPβ)-NFκB signaling pathway in APP/PS1 mice [81][40].

5. Effects of Carnosic Acid in Models of Neuronal Injury

Intriguingly, CA also alleviated symptoms of metabolic-disease-induced brain injury through the modulation of inflammatory responses. In a high-fat-diet-induced mouse model, CA facilitated a significant decrease in the expression of various pro-inflammatory cytokines regulated by the NF-κB signaling pathway, including interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α). Additionally, it also modulated the apoptotic pathway through the increased expression of anti-apoptotic Bcl-2 and downregulation of the pro-apoptotic protein Bax and matrix metallopeptidase 9 (MMP9) [85][41].
Studies in levodopa-induced dyskinesia revealed that CA was capable of alleviating the detrimental effects of excessive levodopa through the attenuation of apoptotic cell death via the modulation of ERK1/2-c-Jun and induction of parkin [86][42]. It also attenuated inflammation, mitochondrial damage, and oxidative stress in isoflurane-treated neuronal cells through the activation of the AMPK/SIRT1 pathway [87][43]. CA has also been shown to exert anti-inflammatory responses in bone-marrow-derived macrophages through the modulation of the toll-like receptor 2 (TLR2) and MAPK/NF-κB signaling pathway, resulting in a decreased expression of TNF-α, IL-6, and IL-1β [88][44]. The anti-inflammatory response of CA was further demonstrated via an integrated proteomic and bioinformatic study that demonstrated the involvement of CA in the modulation of multiple inflammatory processes, including MAPK, NF-κB, and FoxO signaling pathways [89][45]. CA also inhibits the nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome, which plays a critical role in the pathogenesis of neurodegenerative disorders, including AD and PD and COVID-19, including ‘long-COVID’, thereby representing its therapeutic potential [90][46]. Additionally, its neuroprotective role in the prevention of prion protein (PrP) aggregation in cellular models as well as disruption of PrP aggregates in cell-free assays [91][47], raises interesting possibilities for considering CA as a potential adjuvant candidate against prion diseases, including Creutzfeldt–Jakob disease (CJD), Gerstmann–Straussler–Scheinker disease (GSS), and fatal familial insomnia (FFI).
Collectively, these studies demonstrate the cytoprotective characteristics afforded by CA and support its use as both a prophylactic and a neuroprotective compound that warrants continued investigation in diseases of the nervous system (summarized in Table 1).
Table 1.
Neuroprotective effects of carnosic acid and its associated mechanisms of action.

References

  1. Levine, B.; Klionsky, D.J. Development by self-digestion: Molecular mechanisms and biological functions of autophagy. Dev. Cell 2004, 6, 463–477.
  2. Levine, B.; Kroemer, G. Autophagy in the pathogenesis of disease. Cell 2008, 132, 27–42.
  3. Tan, C.C.; Yu, J.T.; Tan, M.S.; Jiang, T.; Zhu, X.C.; Tan, L. Autophagy in aging and neurodegenerative diseases: Implications for pathogenesis and therapy. Neurobiol. Aging 2014, 35, 941–957.
  4. Murrow, L.; Debnath, J. Autophagy as a stress-response and quality-control mechanism: Implications for cell injury and human disease. Annu. Rev. Pathol. 2013, 8, 105–137.
  5. Liu, J.; Su, H.; Qu, Q.M. Carnosic Acid Prevents Beta-Amyloid-Induced Injury in Human Neuroblastoma SH-SY5Y Cells via the Induction of Autophagy. Neurochem. Res. 2016, 41, 2311–2323.
  6. Shibata, S.; Ishitobi, H.; Miyaki, S.; Kawaoka, T.; Kayashima, T.; Matsubara, K. Carnosic acid protects starvation-induced SH-SY5Y cell death through Erk1/2 and Akt pathways, autophagy, and FoxO3a. Int. J. Food Sci. Nutr. 2016, 67, 977–982.
  7. Shimura, H.; Hattori, N.; Kubo, S.; Mizuno, Y.; Asakawa, S.; Minoshima, S.; Shimizu, N.; Iwai, K.; Chiba, T.; Tanaka, K.; et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat. Genet. 2000, 25, 302–305.
  8. Kitada, T.; Asakawa, S.; Hattori, N.; Matsumine, H.; Yamamura, Y.; Minoshima, S.; Yokochi, M.; Mizuno, Y.; Shimizu, N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998, 392, 605–608.
  9. Farrer, M.; Chan, P.; Chen, R.; Tan, L.; Lincoln, S.; Hernandez, D.; Forno, L.; Gwinn-Hardy, K.; Petrucelli, L.; Hussey, J.; et al. Lewy bodies and parkinsonism in families with parkin mutations. Ann. Neurol. 2001, 50, 293–300.
  10. Pramstaller, P.P.; Schlossmacher, M.G.; Jacques, T.S.; Scaravilli, F.; Eskelson, C.; Pepivani, I.; Hedrich, K.; Adel, S.; Gonzales-McNeal, M.; Hilker, R.; et al. Lewy body Parkinson’s disease in a large pedigree with 77 Parkin mutation carriers. Ann. Neurol. 2005, 58, 411–422.
  11. Lin, C.Y.; Tsai, C.W.; Tsai, C.W. Carnosic acid protects SH-SY5Y cells against 6-hydroxydopamine-induced cell death through upregulation of parkin pathway. Neuropharmacology 2016, 110, 109–117.
  12. Lonskaya, I.; Shekoyan, A.R.; Hebron, M.L.; Desforges, N.; Algarzae, N.K.; Moussa, C.E. Diminished parkin solubility and co-localization with intraneuronal amyloid-beta are associated with autophagic defects in Alzheimer’s disease. J. Alzheimers Dis. 2013, 33, 231–247.
  13. Lin, C.Y.; Tsai, C.W. Carnosic Acid Attenuates 6-Hydroxydopamine-Induced Neurotoxicity in SH-SY5Y Cells by Inducing Autophagy Through an Enhanced Interaction of Parkin and Beclin1. Mol. Neurobiol. 2017, 54, 2813–2822.
  14. Lin, C.Y.; Tsai, C.W. PINK1/parkin-mediated mitophagy pathway is related to neuroprotection by carnosic acid in SH-SY5Y cells. Food Chem. Toxicol. 2019, 125, 430–437.
  15. Lin, C.Y.; Chen, W.J.; Fu, R.H.; Tsai, C.W. Upregulation of OPA1 by carnosic acid is mediated through induction of IKKgamma ubiquitination by parkin and protects against neurotoxicity. Food Chem. Toxicol. 2020, 136, 110942.
  16. Lin, C.Y.; Huang, Y.N.; Fu, R.H.; Liao, Y.H.; Kuo, T.Y.; Tsai, C.W. Promotion of mitochondrial biogenesis via the regulation of PARIS and PGC-1alpha by parkin as a mechanism of neuroprotection by carnosic acid. Phytomedicine 2021, 80, 153369.
  17. Olufunmilayo, E.O.; Gerke-Duncan, M.B.; Holsinger, R.M.D. Oxidative Stress and Antioxidants in Neurodegenerative disorders. Antioxidants, 2023; under review.
  18. Hou, C.W.; Lin, Y.T.; Chen, Y.L.; Wang, Y.H.; Chou, J.L.; Ping, L.Y.; Jeng, K.C. Neuroprotective effects of carnosic acid on neuronal cells under ischemic and hypoxic stress. Nutr. Neurosci. 2012, 15, 257–263.
  19. Wu, C.R.; Tsai, C.W.; Chang, S.W.; Lin, C.Y.; Huang, L.C.; Tsai, C.W. Carnosic acid protects against 6-hydroxydopamine-induced neurotoxicity in in vivo and in vitro model of Parkinson’s disease: Involvement of antioxidative enzymes induction. Chem. Biol. Interact. 2015, 225, 40–46.
  20. AlKahtane, A.A.; Ghanem, E.; Bungau, S.G.; Alarifi, S.; Ali, D.; AlBasher, G.; Alkahtani, S.; Aleya, L.; Abdel-Daim, M.M. Carnosic acid alleviates chlorpyrifos-induced oxidative stress and inflammation in mice cerebral and ocular tissues. Environ. Sci. Pollut. Res. Int. 2020, 27, 11663–11670.
  21. De Oliveira, M.R.; Peres, A.; Ferreira, G.C.; Schuck, P.F.; Bosco, S.M. Carnosic Acid Affords Mitochondrial Protection in Chlorpyrifos-Treated SH-SY5Y Cells. Neurotox. Res. 2016, 30, 367–379.
  22. Iorio, R.; Celenza, G.; Petricca, S. Multi-Target Effects of ss-Caryophyllene and Carnosic Acid at the Crossroads of Mitochondrial Dysfunction and Neurodegeneration: From Oxidative Stress to Microglia-Mediated Neuroinflammation. Antioxidants 2022, 11, 1199.
  23. Park, J.A.; Kim, S.; Lee, S.Y.; Kim, C.S.; Kim, D.K.; Kim, S.J.; Chun, H.S. Beneficial effects of carnosic acid on dieldrin-induced dopaminergic neuronal cell death. Neuroreport 2008, 19, 1301–1304.
  24. Teng, L.; Fan, L.; Peng, Y.; He, X.; Chen, H.; Duan, H.; Yang, F.; Lin, D.; Lin, Z.; Li, H.; et al. Carnosic Acid Mitigates Early Brain Injury After Subarachnoid Hemorrhage: Possible Involvement of the SIRT1/p66shc Signaling Pathway. Front. Neurosci. 2019, 13, 26.
  25. Shan, W.; Gao, L.; Zeng, W.; Hu, Y.; Wang, G.; Li, M.; Zhou, J.; Ma, X.; Tian, X.; Yao, J. Activation of the SIRT1/p66shc antiapoptosis pathway via carnosic acid-induced inhibition of miR-34a protects rats against nonalcoholic fatty liver disease. Cell Death Dis. 2015, 6, e1833.
  26. Tsai, C.W.; Lin, C.Y.; Lin, H.H.; Chen, J.H. Carnosic acid, a rosemary phenolic compound, induces apoptosis through reactive oxygen species-mediated p38 activation in human neuroblastoma IMR-32 cells. Neurochem. Res. 2011, 36, 2442–2451.
  27. Parihar, M.S.; Hemnani, T. Alzheimer’s disease pathogenesis and therapeutic interventions. J. Clin. Neurosci. 2004, 11, 456–467.
  28. Gandy, S. The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease. J. Clin. Investig. 2005, 115, 1121–1129.
  29. Mattson, M.P. Pathways towards and away from Alzheimer’s disease. Nature 2004, 430, 631–639.
  30. Furukawa, K.; Sopher, B.L.; Rydel, R.E.; Begley, J.G.; Pham, D.G.; Martin, G.M.; Fox, M.; Mattson, M.P. Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain. J. Neurochem. 1996, 67, 1882–1896.
  31. Meziane, H.; Dodart, J.C.; Mathis, C.; Little, S.; Clemens, J.; Paul, S.M.; Ungerer, A. Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice. Proc. Natl. Acad. Sci. USA 1998, 95, 12683–12688.
  32. Stein, T.D.; Anders, N.J.; DeCarli, C.; Chan, S.L.; Mattson, M.P.; Johnson, J.A. Neutralization of transthyretin reverses the neuroprotective effects of secreted amyloid precursor protein (APP) in APPSW mice resulting in tau phosphorylation and loss of hippocampal neurons: Support for the amyloid hypothesis. J. Neurosci. 2004, 24, 7707–7717.
  33. Meng, P.; Yoshida, H.; Matsumiya, T.; Imaizumi, T.; Tanji, K.; Xing, F.; Hayakari, R.; Dempoya, J.; Tatsuta, T.; Aizawa-Yashiro, T.; et al. Carnosic acid suppresses the production of amyloid-beta 1-42 by inducing the metalloprotease gene TACE/ADAM17 in SH-SY5Y human neuroblastoma cells. Neurosci. Res. 2013, 75, 94–102.
  34. Yoshida, H.; Meng, P.; Matsumiya, T.; Tanji, K.; Hayakari, R.; Xing, F.; Wang, L.; Tsuruga, K.; Tanaka, H.; Mimura, J.; et al. Carnosic acid suppresses the production of amyloid-beta 1-42 and 1-43 by inducing an alpha-secretase TACE/ADAM17 in U373MG human astrocytoma cells. Neurosci. Res. 2014, 79, 83–93.
  35. Liu, W.Y.; Li, Y.; Li, Y.; Xu, L.Z.; Jia, J.P. Carnosic Acid Attenuates AbetaOs-Induced Apoptosis and Synaptic Impairment via Regulating NMDAR2B and Its Downstream Cascades in SH-SY5Y Cells. Mol. Neurobiol. 2023, 60, 133–144.
  36. Meng, P.; Yoshida, H.; Tanji, K.; Matsumiya, T.; Xing, F.; Hayakari, R.; Wang, L.; Tsuruga, K.; Tanaka, H.; Mimura, J.; et al. Carnosic acid attenuates apoptosis induced by amyloid-beta 1-42 or 1-43 in SH-SY5Y human neuroblastoma cells. Neurosci. Res. 2015, 94, 1–9.
  37. Azad, N.; Rasoolijazi, H.; Joghataie, M.T.; Soleimani, S. Neuroprotective effects of carnosic Acid in an experimental model of Alzheimer’s disease in rats. Cell J. 2011, 13, 39–44.
  38. Rasoolijazi, H.; Azad, N.; Joghataei, M.T.; Kerdari, M.; Nikbakht, F.; Soleimani, M. The protective role of carnosic acid against beta-amyloid toxicity in rats. Sci. World J. 2013, 2013, 917082.
  39. Chen, Y.; Wang, Y.; Qin, Q.; Zhang, Y.; Xie, L.; Xiao, J.; Cao, Y.; Su, Z.; Chen, Y. Carnosic acid ameliorated Abeta-mediated (amyloid-beta peptide) toxicity, cholinergic dysfunction and mitochondrial defect in Caenorhabditis elegans of Alzheimer’s Model. Food Funct. 2022, 13, 4624–4640.
  40. Yi-Bin, W.; Xiang, L.; Bing, Y.; Qi, Z.; Fei-Tong, J.; Minghong, W.; Xiangxiang, Z.; Le, K.; Yan, L.; Ping, S.; et al. Inhibition of the CEBPbeta-NFkappaB interaction by nanocarrier-packaged Carnosic acid ameliorates glia-mediated neuroinflammation and improves cognitive function in an Alzheimer’s disease model. Cell Death Dis. 2022, 13, 318.
  41. Liu, Y.; Zhang, Y.; Hu, M.; Li, Y.H.; Cao, X.H. Carnosic acid alleviates brain injury through NF-kappaB-regulated inflammation and Caspase-3-associated apoptosis in high fat-induced mouse models. Mol. Med. Rep. 2019, 20, 495–504.
  42. Lai, C.Y.; Lin, C.Y.; Wu, C.R.; Tsai, C.H.; Tsai, C.W. Carnosic Acid Alleviates Levodopa-Induced Dyskinesia and Cell Death in 6-Hydroxydopamine-lesioned Rats and in SH-SY5Y Cells. Front. Pharmacol. 2021, 12, 703894.
  43. Liao, O.; Xie, K.; Zhang, X.; Jiang, W.; Li, W.; Xie, A. Carnosic acid attenuates inflammation, oxidative stress and mitochondrial dysfunction in neurons via activation of AMPK/SIRT1 pathway. Trop. J. Pharm. Res. 2022, 21, 2359–2365.
  44. Park, M.-Y. Carnosic acid disrupts toll-like receptor 2 signaling pathway in Pam 3 CSK 4-stimulated macrophages. Toxicol. Environ. Health Sci. 2015, 7, 224–230.
  45. Wang, L.C.; Wei, W.H.; Zhang, X.W.; Liu, D.; Zeng, K.W.; Tu, P.F. An Integrated Proteomics and Bioinformatics Approach Reveals the Anti-inflammatory Mechanism of Carnosic Acid. Front. Pharmacol. 2018, 9, 370.
  46. Satoh, T.; Trudler, D.; Oh, C.K.; Lipton, S.A. Potential Therapeutic Use of the Rosemary Diterpene Carnosic Acid for Alzheimer’s Disease, Parkinson’s Disease, and Long-COVID through NRF2 Activation to Counteract the NLRP3 Inflammasome. Antioxidants 2022, 11, 124.
  47. Karagianni, K.; Pettas, S.; Kanata, E.; Lioulia, E.; Thune, K.; Schmitz, M.; Tsamesidis, I.; Lymperaki, E.; Xanthopoulos, K.; Sklaviadis, T.; et al. Carnosic Acid and Carnosol Display Antioxidant and Anti-Prion Properties in In Vitro and Cell-Free Models of Prion Diseases. Antioxidants 2022, 11, 726.
  48. Lipton, S.A.; Rezaie, T.; Nutter, A.; Lopez, K.M.; Parker, J.; Kosaka, K.; Satoh, T.; McKercher, S.R.; Masliah, E.; Nakanishi, N. Therapeutic advantage of pro-electrophilic drugs to activate the Nrf2/ARE pathway in Alzheimer’s disease models. Cell Death Dis. 2016, 7, e2499.
  49. Satoh, T.; Izumi, M.; Inukai, Y.; Tsutsumi, Y.; Nakayama, N.; Kosaka, K.; Shimojo, Y.; Kitajima, C.; Itoh, K.; Yokoi, T.; et al. Carnosic acid protects neuronal HT22 Cells through activation of the antioxidant-responsive element in free carboxylic acid- and catechol hydroxyl moieties-dependent manners. Neurosci. Lett. 2008, 434, 260–265.
  50. Tamaki, Y.; Tabuchi, T.; Takahashi, T.; Kosaka, K.; Satoh, T. Activated glutathione metabolism participates in protective effects of carnosic acid against oxidative stress in neuronal HT22 cells. Planta Med. 2010, 76, 683–688.
  51. Kosaka, K.; Yokoi, T. Carnosic acid, a component of rosemary (Rosmarinus officinalis L.), promotes synthesis of nerve growth factor in T98G human glioblastoma cells. Biol. Pharm. Bull. 2003, 26, 1620–1622.
  52. Mimura, J.; Kosaka, K.; Maruyama, A.; Satoh, T.; Harada, N.; Yoshida, H.; Satoh, K.; Yamamoto, M.; Itoh, K. Nrf2 regulates NGF mRNA induction by carnosic acid in T98G glioblastoma cells and normal human astrocytes. J. Biochem. 2011, 150, 209–217.
  53. Mimura, J.; Inose-Maruyama, A.; Taniuchi, S.; Kosaka, K.; Yoshida, H.; Yamazaki, H.; Kasai, S.; Harada, N.; Kaufman, R.J.; Oyadomari, S.; et al. Concomitant Nrf2- and ATF4-activation by Carnosic Acid Cooperatively Induces Expression of Cytoprotective Genes. Int. J. Mol. Sci. 2019, 20, 1706.
  54. Yoshida, H.; Mimura, J.; Imaizumi, T.; Matsumiya, T.; Ishikawa, A.; Metoki, N.; Tanji, K.; Ota, K.; Hayakari, R.; Kosaka, K.; et al. Edaravone and carnosic acid synergistically enhance the expression of nerve growth factor in human astrocytes under hypoxia/reoxygenation. Neurosci. Res. 2011, 69, 291–298.
  55. Chen, J.H.; Ou, H.P.; Lin, C.Y.; Lin, F.J.; Wu, C.R.; Chang, S.W.; Tsai, C.W. Carnosic acid prevents 6-hydroxydopamine-induced cell death in SH-SY5Y cells via mediation of glutathione synthesis. Chem. Res. Toxicol. 2012, 25, 1893–1901.
  56. Miller, D.M.; Singh, I.N.; Wang, J.A.; Hall, E.D. Administration of the Nrf2-ARE activators sulforaphane and carnosic acid attenuates 4-hydroxy-2-nonenal-induced mitochondrial dysfunction ex vivo. Free Radic. Biol. Med. 2013, 57, 1–9.
  57. Miller, D.M.; Singh, I.N.; Wang, J.A.; Hall, E.D. Nrf2-ARE activator carnosic acid decreases mitochondrial dysfunction, oxidative damage and neuronal cytoskeletal degradation following traumatic brain injury in mice. Exp. Neurol. 2015, 264, 103–110.
  58. Zhang, D.; Lee, B.; Nutter, A.; Song, P.; Dolatabadi, N.; Parker, J.; Sanz-Blasco, S.; Newmeyer, T.; Ambasudhan, R.; McKercher, S.R.; et al. Protection from cyanide-induced brain injury by the Nrf2 transcriptional activator carnosic acid. J. Neurochem. 2015, 133, 898–908.
  59. Kosaka, K.; Mimura, J.; Itoh, K.; Satoh, T.; Shimojo, Y.; Kitajima, C.; Maruyama, A.; Yamamoto, M.; Shirasawa, T. Role of Nrf2 and p62/ZIP in the neurite outgrowth by carnosic acid in PC12h cells. J. Biochem. 2010, 147, 73–81.
  60. Cheng, J.; Xu, T.; Xun, C.; Guo, H.; Cao, R.; Gao, S.; Sheng, W. Carnosic acid protects against ferroptosis in PC12 cells exposed to erastin through activation of Nrf2 pathway. Life Sci. 2021, 266, 118905.
  61. Samy, D.M.; Mostafa, D.K.; Saleh, S.R.; Hassaan, P.S.; Zeitoun, T.M.; Ammar, G.A.G.; Elsokkary, N.H. Carnosic Acid Mitigates Depression-Like Behavior in Ovariectomized Mice via Activation of Nrf2/HO-1 Pathway. Mol. Neurobiol. 2023, 60, 610–628.
  62. Lin, C.Y.; Chen, J.H.; Fu, R.H.; Tsai, C.W. Induction of Pi form of glutathione S-transferase by carnosic acid is mediated through PI3K/Akt/NF-kappaB pathway and protects against neurotoxicity. Chem. Res. Toxicol. 2014, 27, 1958–1966.
  63. De Oliveira, M.R.; Ferreira, G.C.; Schuck, P.F.; Dal Bosco, S.M. Role for the PI3K/Akt/Nrf2 signaling pathway in the protective effects of carnosic acid against methylglyoxal-induced neurotoxicity in SH-SY5Y neuroblastoma cells. Chem. Biol. Interact. 2015, 242, 396–406.
  64. De Oliveira, M.R.; Peres, A.; Ferreira, G.C.; Schuck, P.F.; Gama, C.S.; Bosco, S.M.D. Carnosic Acid Protects Mitochondria of Human Neuroblastoma SH-SY5Y Cells Exposed to Paraquat Through Activation of the Nrf2/HO-1Axis. Mol. Neurobiol. 2017, 54, 5961–5972.
  65. De Oliveira, M.R.; Duarte, A.R.; Chenet, A.L.; de Almeida, F.J.S.; Andrade, C.M.B. Carnosic Acid Pretreatment Attenuates Mitochondrial Dysfunction in SH-SY5Y Cells in an Experimental Model of Glutamate-Induced Excitotoxicity. Neurotox. Res. 2019, 36, 551–562.
  66. Lin, C.Y.; Fu, R.H.; Chou, R.H.; Chen, J.H.; Wu, C.R.; Chang, S.W.; Tsai, C.W. Inhibition of JNK by pi class of glutathione S-transferase through PKA/CREB pathway is associated with carnosic acid protection against 6-hydroxydopamine-induced apoptosis. Food Chem. Toxicol. 2017, 103, 194–202.
  67. Fu, R.H.; Huang, L.C.; Lin, C.Y.; Tsai, C.W. Modulation of ARTS and XIAP by Parkin Is Associated with Carnosic Acid Protects SH-SY5Y Cells against 6-Hydroxydopamine-Induced Apoptosis. Mol. Neurobiol. 2018, 55, 1786–1794.
  68. Feng, M.; Cui, D.; Li, Y.; Shi, J.; Xiang, L.; Bian, H.; Ma, Z.; Xia, W.; Wei, G. Carnosic Acid Reverses the Inhibition of ApoE4 on Cell Surface Level of ApoER2 and Reelin Signaling Pathway. J. Alzheimers Dis. 2020, 73, 517–528.
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