Molecular Mechanisms of Berberine’s Neuroprotection: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Erjie Tian
,
Gaurav Sharma
,
Chongshan Dai

Berberine (BBR), an isoquinoline alkaloid natural product, is isolated primarily from Coptis chinensis and other Berberis plants. BBR possesses various bioactivities, including antioxidant, anti-inflammation, anticancer, immune-regulation, and antimicrobial activities. Growing scientific evidence underscores BBR’s substantial neuroprotective potential, prompting increased interest and scrutiny.

  • berberine
  • neuroprotective effects
  • molecular mechanisms

1. Inhibition of Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis

Growing evidence underscores the pivotal role of oxidative stress in the initiation and progression of neurodegenerative disorders [1][2][3][4][5][6][7][8][9][10][11][12]. Excessive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) under oxidative stress conditions can induce lipid peroxidation, protein oxidation, protein nitration, and glycol oxidation, culminating in membrane damage, cytoskeletal abnormalities, and DNA damage within neural tissues [1][2][3][4][5][6][7][8][9][10][11][12]. Consequently, antioxidant supplementation has emerged as an effective therapeutic strategy for neurodegenerative diseases [13][14][15][16].
Numerous studies have shed light on the potent antioxidant properties of BBR, making it a promising option for treating neurodegenerative diseases [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. In vitro investigations have demonstrated its ability to scavenge peroxynitrite (ONOO−), nitric oxide (NO), hydroxyl radical (OH•), superoxide anion (O2•−), and sodium nitroprusside, cisplatin, and Fe2+-induced lipid peroxidation (LPO) [34]. Using in vitro 2, 2-diphenyl-1-picrylhydrazyl radical (DPPH) and 2, 2-azinobis (3-ethylbenzothiazoline-6-sulfonate) radical tests showed that the half-maximal inhibitory concentrations (IC50s) of BBR are both about 0.3 mg/mL [35]. In addition, it was also found that the IC50s of BBR for NO radical scavenging, Fe2+ chelation, and OH• radical scavenging are 0.17 mg/mL, 0.12 mg/mL, and 0.11 mg/mL, respectively [35]. Notably, ONOO− is a potent oxidative and nitrating reagent capable of damaging various intracellular macromolecules, including proteins, lipids, and DNA. BBR effectively reduces superoxide levels in macrophages mediated by NADPH oxidase, restoring cellular redox balance by selectively inhibiting gp91phox expression and enhancing antioxidant enzyme activities, such as superoxide dismutase (SOD) and catalase (CAT), thereby mitigating oxidative-stress-induced cytotoxicity and brain injury [21][36]. Animal studies have corroborated these findings, showing that BBR supplementation significantly reduces malondialdehyde (MDA) levels, enhances SOD and CAT activities, and inhibits caspase activities in the hippocampus tissues of rats, thereby attenuating neurodegeneration induced by two-vessel occlusion [27]. Additionally, BBR has been shown to prevent mitochondrial ROS generation by targeting the N-methyl-D-aspartate-receptor (NMDA)R1/NADPH oxidase 3 (NOX3) pathway, protecting spiral ganglion cells from cytomegalovirus-induced apoptosis [37].
Mitochondria, being both the main targets and producers of ROS, play a central role in oxidative-stress-related neurodegeneration [38]. Studies have demonstrated that ROS production is regulated by various antioxidant defense pathways, including the PI3K/Akt pathway, Nrf2 pathway, and PPAR pathway [39][40][41]. Nrf2, a key regulator of antioxidant defense, transcriptionally controls the expression of numerous protective genes in response to oxidative stress [42]. Although direct interactions between BBR and Nrf2 require further investigation, studies have shown that BBR supplementation activates Nrf2 and its downstream target, heme oxygenase-1 (HO-1), exerting neuroprotective effects [42]. Many studies have reported that the Nrf2–antioxidant response element axis is a critical target against oxidative stress in neurodegenerative diseases [43]. Albeit it still lacks the direct evidence of BBR interaction with Nrf2, some studies have illustrated that BBR supplementation could activate the expression of Nrf2 and its downstream gene HO-1, exhibiting its neuroprotective effects [39]. Activation of the Akt signaling pathway by BBR inhibits ROS production, protecting against oxidative stress induced by various agents [44][45]. Consistently, it has been reported that BBR supplementation could alleviate rotenone-induced ROS production in human neuroblastoma cells (i.e., SH-SY5Y cells) via the inhibition of mitochondrial dysfunction through activating the PI3K/Akt signaling pathway [32]. Moreover, BBR has been reported to alleviate rotenone-induced ROS production via the activation of Nrf2 and HO-1 expression, safeguarding against high-glucose-induced cell apoptosis [46]. Hsu et al. demonstrated that BBR activates Nrf2 nuclear translocation and protects NSC34 motor neuron-like cells from oxidative damage through the activation of PI3K/Akt-dependent cytoprotective pathways [47]. Recent findings highlight BBR as a potent ligand of PPARδ, promoting Nrf2 and NQO1 expression and consequently mitigating oxidative stress and brain injury in a mouse model of middle cerebral artery occlusion (MCAO) [41]. In short, the antioxidant defense function of BBR against neurotoxic effects caused by oxidative stress mainly depends on its free radical scavenging ability and the activation of endogenous antioxidant signaling pathways, such as the Nrf2, PI3K/Akt, and PPARδ pathways.
Mitochondrial dysfunction, stemming from excessive reactive oxygen species (ROS) production, triggers a cascade of events, including ATP depletion, the opening of mitochondrial permeability transition pores, caspase activation, and cellular apoptosis [48]. The opening of mitochondrial permeability transition pores is regulated by various proteins and signaling networks, including mitochondrial membrane potential, mitochondrial Ca2+ signals, and members of the Bcl-2 family (e.g., the antiapoptotic B-cell lymphoma-extra-large [Bcl-XL] and Bcl-2; the proapoptotic members of the family: Bcl-2-associated X protein [BAX], Bcl-2 antagonist/killer 1 [BAK1], and Bcl-2-associated agonist of cell death [BAD]) [49]. BBR supplementation has been shown to upregulate mitochondrial membrane potential and ATP levels, protecting against amyloid-β-induced mitochondrial dysfunction and cell apoptosis in primary cultured hippocampal neurons [50]. BBR inhibits the release of proapoptotic factors like cytochrome c and apoptosis-inducing factors (AIFs) in response to oxygen–glucose deprivation (OGD), safeguarding against ischemic brain injury [51]. In a rat model, Singh et al. found that oral BBR supplementation at the doses of 10 or 20 mg/kg/day for 19 days could significantly improve the mitochondrial complex (I, II, and IV) activities and inhibit the activation of caspase-3 in brain tissues, followed by the amelioration of cerebral ischemia-induced brain injury [52]. The neuroprotective effect of BBR against ischemia-induced brain injury involves the activation of the Akt/GSK3β/ERK1/2 signal pathway and the inhiation of the JNK/caspase-3 pathway [53].

2. Blockade of Inflammatory Response and Necroptosis

Previous studies have convincingly established that mitigating neuroinflammation could mitigate neuronal loss and decrease the morbidity associated with neurodegenerative disorders [54][55][56][57]. Neuroinflammation, characterized by the chronic activation of microglia and astrocytes, can result from various factors such as traumatic brain injury, microbial infection, drugs, neurotoxins, or toxic metabolites [54][55][56][57]. In the context of neurodegenerative diseases, the activation of microglia and astrocytes often leads to the secretion of multiple proinflammatory mediators and neurotoxic cytokines. This, in turn, fuels a detrimental cycle of neuronal damage and neuroinflammation, ultimately driving the chronic progression of neurodegenerative conditions [54][55][56][57].
Berberine (BBR) stands out as a promising agent for combating neuroinflammation, effectively regulating the inflammatory response triggered by infections, toxins, aging, or ischemia–reperfusion through multiple signaling pathways [58][59][60][61][62]. In an in vitro model simulating the pathology of Alzheimer’s disease, BBR alleviates neuroinflammatory response by reducing the production of proinflammatory cytokines in microglia [63]. Furthermore, BBR partially ameliorates cognitive dysfunction induced by lipopolysaccharide (LPS) by attenuating neuroinflammation [64]. Jia et al. found that BBR supplementation could inhibit Aβ-induced microglia inflammation by suppressing the activation of the NF-κB and MAPK signaling pathways [65]. Zhang et al. found that BBR could reduce ischemic brain injury and neuroinflammatory response via increasing the activation of the Akt/glycogen synthase kinase (GSK) signaling pathway and inhibiting the NF-κB pathway [66]. BBR supplementation could reduce TLR4/MyD88/NF-κB signaling transduction and attenuate neuronal death induced by microglial-conditioned media [61]. BBR effectively inhibits the inflammatory activation of rat brain microglia by inactivating the NF-κB/iNOS/NO pathway or activating the AMPK pathway [59][67][68]. Additionally, several studies have reported that BBR directly upregulates the expression of anti-inflammatory factors (e.g., interleukin (IL)-4 [IL-4] and IL-10) while inhibiting the expression of proinflammatory factors, IL-1β, IL-6, and tumor necrosis factor-α (TNF-α)), displaying therapeutic effects against neuroinflammatory diseases in both in vitro and in vivo settings [68][69][70][71].
Necroptosis, a regulated form of cell death distinct from apoptosis, is known to induce marked inflammatory responses and adaptive immunity effects in the body [72]. Previous studies have indicated that BBR may act as a necroptosis inducer in cancer cells, showcasing potential anti-tumor effects [73][74][75]. BBR usually plays a neuroprotective role in the treatments for neurological diseases and neuronal cells inhibiting necroptosis [76]. Ou et al. demonstrated that BBR treatment could significantly inhibit the expression of receptor-interacting protein 1 (RIP1) and RIP3, two key regulators of necroptosis, attenuating the neuroinflammatory response and cognitive impairment in the hippocampus tissues in rats exposed to excessive L-arginine [76].

3. Induction of Autophagy

Berberine (BBR) exhibits neuroprotective qualities by inducing autophagy and facilitating the clearance of toxic aggregate proteins [77][78][79]. BBR has been found to trigger autophagy in various cell types, including macrophages, lymphoblastic leukemia cells, retinal cells, and neuronal cells, as well as in various tissues such as the liver, lung, kidney, stomach, breast, and myocardium [80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96].
One of BBR’s mechanisms of neuroprotection involves promoting autophagy to eliminate misfolded proteins. Several studies have also found that BBR supplementation could effectively improve the motor dysfunction of mice with Huntingtin’s diseases via promoting the degradation of mutant Huntingtin protein through enhancing cell autophagy [78][97]. This process ultimately alleviates motor dysfunction and extends the survival period in a mouse model of Huntington’s disease [78]. Similarly, in an APP/tau/PS1 triple-transgenic mouse model of Alzheimer’s disease, BBR treatment could significantly improve the cognitive impairment of mice by promoting autophagy while inhibiting the production of β-amyloid (Aβ) through suppressing β-site APP cleavage enzyme 1 (BACE1) expression [79]. Moreover, in another study, data showed that BBR reduced the production of Aβ and the expression of the BACE1 protein by activating AMPK in nerve cells [98]. Interestingly, a great many studies have indicated that autophagy is AMPK-dependent or triggered via the AMPK/mTOR pathway [99][100]. Consequently, BBR may activate autophagy by the AMPK signal

4. Modulation of Neurotransmitters

Neurotransmitters are pivotal in facilitating intraneuronal communication and neurobehavioral functions [101]. BBR has demonstrated the ability to inhibit the activity of acetylcholinesterase, butyrylcholinesterase, and monoamine oxidases (MAOs), which play vital roles in regulating the levels of neurotransmitters [102][103]. For example, MAO-A and MAO-B, two isozymes of MAOs, are principally responsible for the degradation of various amine neurotransmitters, including DA, norepinephrine (NE), serotonin (5-HT), and epinephrine, all of which are crucial in the development of neurodegenerative diseases [104][105].
A previous study showed that oral administration of BBR at the final doses of 10 or 20 mg/kg could show a potent antidepressant-like effect in mice via upregulation of the levels of NA and 5-HT in the hippocampus and frontal cortex [102]. Additionally, BBR has been reported to significantly enhance DA levels in the brains of mice with Parkinson’s disease, attributed to increased gut Enterococcus abundance, thereby ameliorating Parkinson’s disease symptoms [106]. BBR administration has also been shown to suppress cholinesterase activity, thereby protecting the cholinergic system, and enhancing memory function in diabetic rats [33][104]. Glutamate is a primary excitatory neurotransmitter in the brains of animals and humans. N-methyl-d-aspartate (NMDA) is its receptor. Furthermore, BBR treatment has been found to protect against MK-801-induced neurodegeneration in rat brains by enhancing NMDA-mediated activity-dependent cell survival [107]. Similarly, BBR administration has been shown to significantly reduce the release of glutamate from rats’ cortical synaptosomes via inhibition of presynaptic Cav2.1 channels as well as the downregulation of the ERK/synapsin I signaling cascade [108].

5. Modulation of CYP450 Enzyme Activities

Recent studies have underscored the critical role that cytochrome P450 (CYP450) may play in the development or treatment of neurological diseases based on its effects on temperature control, maintenance of brain cholesterol homeostasis, neuropeptide release, and regulation of neurotransmitter levels [109]. It has been reported that BBR has a potent regulatory effect on CYP450 activities in liver, heart, kidney, and breast tissues [110][111][112][113][114][115][116][117][118][119][120].
Earlier investigations revealed that BBR could inhibit the activities of CYP1 enzymes, including CYP1A1, CYP1A2, and CYP1B1, with a stronger preference for CYP1B1 [121]. CYP1B1 has been reported to make an important contribution in the procession of various neurological disorders based on its regulated effects on the production of ROS and redox homeostasis [122]. It has been demonstrated that the deficiency of CYP1B1 could protect retinal astrocytes against oxidative stress and inflammation [123]. In addition, in a human clinical trial, researchers found that repeated administration of BBR (oral administration at a dose of 300 mg, three times daily, for 14 days) decreased CYP2D6, CYP2C9, and CYP3A4 activities [115][124]. Based on the inhibitory effects of BBR on the activities of the CYP3A4 enzyme, BBR significantly increases the blood concentration of cyclosporine when co-administrated [125]. In addition, p-glycoprotein (P-gp)-mediated gut efflux properties are responsible for the reduced bioavailability of BBR and verapamil, a p-gp inhibitor, and co-treatment could significantly enhance the neuroprotective effect of BBR against streptozotocin-induced cognitive dysfunction in a rat model [126].

6. Others

Berberine (BBR) has demonstrated notable neuroprotective potential through various molecular pathways. Notably, it has been reported that BBR enhances synaptic plasticity by activating the cAMP response element-binding protein (CREB), leading to the production of brain-derived neurotrophic factor (BDNF) through the upregulation of SIRT1. This, in turn, contributes to the amelioration of cognitive impairment induced by chemotherapy drugs, such as doxorubicin [127]. In a transient middle cerebral artery occlusion rat model, BBR administration could induce gut–brain axis signal transmission and stimulate the vague nerve by inducing the production of intestinal hydrogen through the regulation of gut microbiota, finally offering neuroprotection [128]. Furthermore, BBR treatment has also been shown to reduce hippocampus neuronal damage by inhibiting the expression of the matrix metalloproteinase-9 protein and gelatinase activities and downregulating the expression of laminin and neuronal nuclei antigen (NeuN) proteins in the hippocampal CA1 and CA2 areas [129]. These functions also contribute to the therapeutic effects of BBR against multiple sclerosis disease [130]. Another study by Wu et al. highlights the neuroprotective potential of BBR by blocking neuronal ATP-sensitive K+ channels in substantia nigra pars compacta dopaminergic neurons [131]. BBR has also shown promise in enhancing nerve growth factor (NGF) expression, which promotes Nrf2- and Akt-related neurite outgrowth and differentiation, thus protecting against oxidative stress and neuroinflammatory responses [46][132][133].

This entry is adapted from the peer-reviewed paper 10.3390/antiox12101883

References

  1. Teleanu, D.M.; Niculescu, A.G.; Lungu, I.I.; Radu, C.I.; Vladâcenco, O.; Roza, E.; Costăchescu, B.; Grumezescu, A.M.; Teleanu, R.I. An Overview of Oxidative Stress, Neuroinflammation, and Neurodegenerative Diseases. Int. J. Mol. Sci. 2022, 23, 5938.
  2. Vejux, A. Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules. Int. J. Mol. Sci. 2021, 22, 13657.
  3. Saleem, U.; Sabir, S.; Niazi, S.G.; Naeem, M.; Ahmad, B. Role of Oxidative Stress and Antioxidant Defense Biomarkers in Neurodegenerative Diseases. Crit. Rev. Eukaryot. Gene Expr. 2020, 30, 311–322.
  4. Singh, A.; Kukreti, R.; Saso, L.; Kukreti, S. Oxidative Stress: A Key Modulator in Neurodegenerative Diseases. Molecules 2019, 24, 1583.
  5. Islam, M.T. Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders. Neurol. Res. 2017, 39, 73–82.
  6. Niedzielska, E.; Smaga, I.; Gawlik, M.; Moniczewski, A.; Stankowicz, P.; Pera, J.; Filip, M. Oxidative Stress in Neurodegenerative Diseases. Mol. Neurobiol. 2016, 53, 4094–4125.
  7. Kim, G.H.; Kim, J.E.; Rhie, S.J.; Yoon, S. The Role of Oxidative Stress in Neurodegenerative Diseases. Exp. Neurobiol. 2015, 24, 325–340.
  8. Thanan, R.; Oikawa, S.; Hiraku, Y.; Ohnishi, S.; Ma, N.; Pinlaor, S.; Yongvanit, P.; Kawanishi, S.; Murata, M. Oxidative stress and its significant roles in neurodegenerative diseases and cancer. Int. J. Mol. Sci. 2014, 16, 193–217.
  9. Li, J.; Ao, W.; Li, W.; Jiang, Z.-G.; Ghanbari, H.A. Oxidative stress and neurodegenerative disorders. Int. J. Mol. Sci. 2013, 14, 24438–24475.
  10. Chen, X.; Guo, C.; Kong, J. Oxidative stress in neurodegenerative diseases. Neural Regen. Res. 2012, 7, 376–385.
  11. Uttara, B.; Singh, A.V.; Zamboni, P.; Mahajan, R.T. Oxidative stress and neurodegenerative diseases: A review of upstream and downstream antioxidant therapeutic options. Curr. Neuropharmacol. 2009, 7, 65–74.
  12. Lin, M.T.; Beal, M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006, 443, 787–795.
  13. Fernandes, C.; Oliveira, C.; Benfeito, S.; Soares, P.; Garrido, J.; Borges, F. Nanotechnology and antioxidant therapy: An emerging approach for neurodegenerative diseases. Curr. Med. Chem. 2014, 21, 4311–4327.
  14. Danta, C.C.; Piplani, P. The discovery and development of new potential antioxidant agents for the treatment of neurodegenerative diseases. Expert Opin. Drug Discov. 2014, 9, 1205–1222.
  15. Guerra-Araiza, C.; Álvarez-Mejía, A.L.; Sánchez-Torres, S.; Farfan-García, E.; Mondragón-Lozano, R.; Pinto-Almazán, R.; Salgado-Ceballos, H. Effect of natural exogenous antioxidants on aging and on neurodegenerative diseases. Free Radic. Res. 2013, 47, 451–462.
  16. Tardiolo, G.; Bramanti, P.; Mazzon, E. Overview on the Effects of N-Acetylcysteine in Neurodegenerative Diseases. Molecules 2018, 23, 3305.
  17. Li, Z.; Geng, Y.N.; Jiang, J.D.; Kong, W.J. Antioxidant and anti-inflammatory activities of berberine in the treatment of diabetes mellitus. Evid.-Based Complement. Altern. Med. 2014, 2014, 289264.
  18. Song, D.; Hao, J.; Fan, D. Biological properties and clinical applications of berberine. Front. Med. 2020, 14, 564–582.
  19. Ahmed, T.; Gilani, A.U.; Abdollahi, M.; Daglia, M.; Nabavi, S.F.; Nabavi, S.M. Berberine and neurodegeneration: A review of literature. Pharmacol. Rep. 2015, 67, 970–979.
  20. Zhou, J.Y.; Zhou, S.W. Protective effect of berberine on antioxidant enzymes and positive transcription elongation factor b expression in diabetic rat liver. Fitoterapia 2011, 82, 184–189.
  21. Zhang, Y.; Wang, L.; Li, G.; Gao, J. Berberine-Albumin Nanoparticles: Preparation, Thermodynamic Study and Evaluation Their Protective Effects Against Oxidative Stress in Primary Neuronal Cells as a Model of Alzheimer’s Disease. J. Biomed. Nanotechnol. 2021, 17, 1088–1097.
  22. Yaw, L.S.; Lindsei, S.; Karmin, O. Redox regulation in health and disease—Therapeutic potential of berberine. Food Res. Int. 2011, 44, 2409–2417.
  23. Thirupurasundari, C.J.; Padmini, R.; Devaraj, S.N. Effect of berberine on the antioxidant status, ultrastructural modifications and protein bound carbohydrates in azoxymethane-induced colon cancer in rats. Chem. Biol. Interact. 2009, 177, 190–195.
  24. Tan, Y.; Tang, Q.; Hu, B.R.; Xiang, J.Z. Antioxidant properties of berberine on cultured rabbit corpus cavernosum smooth muscle cells injured by hydrogen peroxide. Acta Pharmacol. Sin. 2007, 28, 1914–1918.
  25. Singh, A.K.; Singh, S.K.; Nandi, M.K.; Mishra, G.; Maurya, A.; Rai, A.; Rai, G.K.; Awasthi, R.; Sharma, B.; Kulkarni, G.T. Berberine: A Plant-derived Alkaloid with Therapeutic Potential to Combat Alzheimer’s disease. Cent. Nerv. Syst. Agents Med. Chem. 2019, 19, 154–170.
  26. Shirwaikar, A.; Shirwaikar, A.; Rajendran, K.; Punitha, I.S. In vitro antioxidant studies on the benzyl tetra isoquinoline alkaloid berberine. Biol. Pharm. Bull. 2006, 29, 1906–1910.
  27. Pirmoradi, Z.; Yadegari, M.; Moradi, A.; Khojasteh, F.; Zare Mehrjerdi, F. Effect of berberine chloride on caspase-3 dependent apoptosis and antioxidant capacity in the hippocampus of the chronic cerebral hypoperfusion rat model. Iran. J. Basic Med. Sci. 2019, 22, 154–159.
  28. Liu, W.H.; Hei, Z.Q.; Nie, H.; Tang, F.T.; Huang, H.Q.; Li, X.J.; Deng, Y.H.; Chen, S.R.; Guo, F.F.; Huang, W.G.; et al. Berberine ameliorates renal injury in streptozotocin-induced diabetic rats by suppression of both oxidative stress and aldose reductase. Chin. Med. J. 2008, 121, 706–712.
  29. Kazaz, I.O.; Mentese, A.; Demir, S.; Kerimoglu, G.; Colak, F.; Bodur, A.; Alver, A.; Kutlu, O.; Turedi, S. Berberine inhibits the ischemia-reperfusion induced testicular injury through decreasing oxidative stress. Am. J. Emerg. Med. 2020, 38, 33–37.
  30. Hsieh, Y.S.; Kuo, W.H.; Lin, T.W.; Chang, H.R.; Lin, T.H.; Chen, P.N.; Chu, S.C. Protective effects of berberine against low-density lipoprotein (LDL) oxidation and oxidized LDL-induced cytotoxicity on endothelial cells. J. Agric. Food Chem. 2007, 55, 10437–10445.
  31. Germoush, M.O.; Mahmoud, A.M. Berberine mitigates cyclophosphamide-induced hepatotoxicity by modulating antioxidant status and inflammatory cytokines. J. Cancer Res. Clin. Oncol. 2014, 140, 1103–1109.
  32. Deng, H.; Jia, Y.; Pan, D.; Ma, Z. Berberine alleviates rotenone-induced cytotoxicity by antioxidation and activation of PI3K/Akt signaling pathway in SH-SY5Y cells. Neuroreport 2020, 31, 41–47.
  33. Bhutada, P.; Mundhada, Y.; Bansod, K.; Tawari, S.; Patil, S.; Dixit, P.; Umathe, S.; Mundhada, D. Protection of cholinergic and antioxidant system contributes to the effect of berberine ameliorating memory dysfunction in rat model of streptozotocin-induced diabetes. Behav. Brain Res. 2011, 220, 30–41.
  34. Yokozawa, T.; Ishida, A.; Kashiwada, Y.; Cho, E.J.; Kim, H.Y.; Ikeshiro, Y. Coptidis Rhizoma: Protective effects against peroxynitrite-induced oxidative damage and elucidation of its active components. J. Pharm. Pharmacol. 2004, 56, 547–556.
  35. Adefegha, S.A.; Oboh, G.; Okeke, B.M. Comparative effects of berberine and piperine on the neuroprotective potential of neostigmine. J. Complement. Integr. Med. 2021, 18, 491–497.
  36. Sarna, L.K.; Wu, N.; Hwang, S.Y.; Siow, Y.L.; Karmin, O. Berberine inhibits NADPH oxidase mediated superoxide anion production in macrophages. Can. J. Physiol. Pharmacol. 2010, 88, 369–378.
  37. Zhuang, W.; Li, T.; Wang, C.; Shi, X.; Li, Y.; Zhang, S.; Zhao, Z.; Dong, H.; Qiao, Y. Berberine exerts antioxidant effects via protection of spiral ganglion cells against cytomegalovirus-induced apoptosis. Free Radic. Biol. Med. 2018, 121, 127–135.
  38. Dai, C.; Tian, E.; Hao, Z.; Tang, S.; Wang, Z.; Sharma, G.; Jiang, H.; Shen, J. Aflatoxin B1 Toxicity and Protective Effects of Curcumin: Molecular Mechanisms and Clinical Implications. Antioxidants 2022, 11, 2031.
  39. Zhang, C.; Li, C.; Chen, S.; Li, Z.; Jia, X.; Wang, K.; Bao, J.; Liang, Y.; Wang, X.; Chen, M.; et al. Berberine protects against 6-OHDA-induced neurotoxicity in PC12 cells and zebrafish through hormetic mechanisms involving PI3K/AKT/Bcl-2 and Nrf2/HO-1 pathways. Redox Biol. 2017, 11, 1–11.
  40. Tian, H.; Kang, Y.M.; Gao, H.L.; Shi, X.L.; Fu, L.Y.; Li, Y.; Jia, X.Y.; Liu, K.L.; Qi, J.; Li, H.B.; et al. Chronic infusion of berberine into the hypothalamic paraventricular nucleus attenuates hypertension and sympathoexcitation via the ROS/Erk1/2/iNOS pathway. Phytomed. Int. J. Phytother. Phytopharm. 2019, 52, 216–224.
  41. Shou, J.W.; Li, X.X.; Tang, Y.S.; Lim-Ho Kong, B.; Wu, H.Y.; Xiao, M.J.; Cheung, C.K.; Shaw, P.C. Novel mechanistic insight on the neuroprotective effect of berberine: The role of PPARδ for antioxidant action. Free Radic. Biol. Med. 2022, 181, 62–71.
  42. Tonelli, C.; Chio, I.I.C.; Tuveson, D.A. Transcriptional Regulation by Nrf2. Antioxid. Redox Signal. 2018, 29, 1727–1745.
  43. Buendia, I.; Michalska, P.; Navarro, E.; Gameiro, I.; Egea, J.; León, R. Nrf2-ARE pathway: An emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases. Pharmacol. Ther. 2016, 157, 84–104.
  44. Li, D.; Dai, C.; Yang, X.; Wang, F.; Yu, X.; Xiao, X.; Tang, S. Critical role of p21 on olaquindox-induced mitochondrial apoptosis and S-phase arrest involves activation of PI3K/AKT and inhibition of Nrf2/HO-1pathway. Food Chem. Toxicol. 2017, 108, 148–160.
  45. Deng, S.; Tang, S.; Zhang, S.; Zhang, C.; Wang, C.; Zhou, Y.; Dai, C.; Xiao, X. Furazolidone induces apoptosis through activating reactive oxygen species-dependent mitochondrial signaling pathway and suppressing PI3K/Akt signaling pathway in HepG2 cells. Food Chem. Toxicol. 2015, 75, 173–186.
  46. Hsu, Y.Y.; Tseng, Y.T.; Lo, Y.C. Berberine, a natural antidiabetes drug, attenuates glucose neurotoxicity and promotes Nrf2-related neurite outgrowth. Toxicol. Appl. Pharmacol. 2013, 272, 787–796.
  47. Hsu, Y.Y.; Chen, C.S.; Wu, S.N.; Jong, Y.J.; Lo, Y.C. Berberine activates Nrf2 nuclear translocation and protects against oxidative damage via a phosphatidylinositol 3-kinase/Akt-dependent mechanism in NSC34 motor neuron-like cells. Eur. J. Pharm. Sci. 2012, 46, 415–425.
  48. Phadwal, K.; Vrahnas, C.; Ganley, I.G.; MacRae, V.E. Mitochondrial Dysfunction: Cause or Consequence of Vascular Calcification? Front. Cell Dev. Biol. 2021, 9, 611922.
  49. Bonora, M.; Giorgi, C.; Pinton, P. Molecular mechanisms and consequences of mitochondrial permeability transition. Nat. Rev. Mol. Cell Biol. 2022, 23, 266–285.
  50. Zhao, C.; Su, P.; Lv, C.; Guo, L.; Cao, G.; Qin, C.; Zhang, W. Berberine Alleviates Amyloid β-Induced Mitochondrial Dysfunction and Synaptic Loss. Oxidative Med. Cell. Longev. 2019, 2019, 7593608.
  51. Zhou, X.Q.; Zeng, X.N.; Kong, H.; Sun, X.L. Neuroprotective effects of berberine on stroke models in vitro and in vivo. Neurosci. Lett. 2008, 447, 31–36.
  52. Singh, D.P.; Chopra, K. Verapamil augments the neuroprotectant action of berberine in rat model of transient global cerebral ischemia. Eur. J. Pharmacol. 2013, 720, 98–106.
  53. Simões Pires, E.N.; Frozza, R.L.; Hoppe, J.B.; Menezes Bde, M.; Salbego, C.G. Berberine was neuroprotective against an in vitro model of brain ischemia: Survival and apoptosis pathways involved. Brain Res. 2014, 1557, 26–33.
  54. Fan, D.; Liu, L.; Wu, Z.; Cao, M. Combating Neurodegenerative Diseases with the Plant Alkaloid Berberine: Molecular Mechanisms and Therapeutic Potential. Curr. Neuropharmacol. 2019, 17, 563–579.
  55. Klegeris, A.; McGeer, P.L. Non-steroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory agents in the treatment of neurodegenerative disease. Curr. Alzheimer Res. 2005, 2, 355–365.
  56. Esposito, E.; Di Matteo, V.; Benigno, A.; Pierucci, M.; Crescimanno, G.; Di Giovanni, G. Non-steroidal anti-inflammatory drugs in Parkinson’s disease. Exp. Neurol. 2007, 205, 295–312.
  57. Apetz, N.; Munch, G.; Govindaraghavan, S.; Gyengesi, E. Natural compounds and plant extracts as therapeutics against chronic inflammation in Alzheimer’s disease--a translational perspective. CNS Neurol. Disord. Drug Targets 2014, 13, 1175–1191.
  58. Wu, X.; Liu, X.; Yang, L.; Wang, Y. Berberine Protects against Neurological Impairments and Blood-Brain Barrier Injury in Mouse Model of Intracerebral Hemorrhage. Neuroimmunomodulation 2021, 29, 317–326.
  59. Lu, D.Y.; Tang, C.H.; Chen, Y.H.; Wei, I.H. Berberine suppresses neuroinflammatory responses through AMP-activated protein kinase activation in BV-2 microglia. J. Cell. Biochem. 2010, 110, 697–705.
  60. Gabet, B.; Kuo, P.C.; Fuentes, S.; Patel, Y.; Adow, A.; Alsakka, M.; Avila, P.; Beam, T.; Yen, J.H.; Brown, D.A. Identification of N-benzyltetrahydroisoquinolines as novel anti-neuroinflammatory agents. Bioorg. Med. Chem. 2018, 26, 5711–5717.
  61. Chen, C.C.; Hung, T.H.; Lee, C.Y.; Wang, L.F.; Wu, C.H.; Ke, C.H.; Chen, S.F. Berberine protects against neuronal damage via suppression of glia-mediated inflammation in traumatic brain injury. PLoS ONE 2014, 9, e115694.
  62. Qin, Z.; Shi, D.D.; Li, W.; Cheng, D.; Zhang, Y.D.; Zhang, S.; Tsoi, B.; Zhao, J.; Wang, Z.; Zhang, Z.J. Berberine ameliorates depression-like behaviors in mice via inhibiting NLRP3 inflammasome-mediated neuroinflammation and preventing neuroplasticity disruption. J. Neuroinflamm. 2023, 20, 54.
  63. Wong, L.R.; Tan, E.A.; Lim, M.E.J.; Shen, W.; Lian, X.L.; Wang, Y.; Chen, L.; Ho, P.C. Functional effects of berberine in modulating mitochondrial dysfunction and inflammatory response in the respective amyloidogenic cells and activated microglial cells—In vitro models simulating Alzheimer’s disease pathology. Life Sci. 2021, 282, 119824.
  64. Sadraie, S.; Kiasalari, Z.; Razavian, M.; Azimi, S.; Sedighnejad, L.; Afshin-Majd, S.; Baluchnejadmojarad, T.; Roghani, M. Berberine ameliorates lipopolysaccharide-induced learning and memory deficit in the rat: Insights into underlying molecular mechanisms. Metab. Brain Dis. 2019, 34, 245–255.
  65. Jia, L.; Liu, J.; Song, Z.; Pan, X.; Chen, L.; Cui, X.; Wang, M. Berberine suppresses amyloid-beta-induced inflammatory response in microglia by inhibiting nuclear factor-kappaB and mitogen-activated protein kinase signalling pathways. J. Pharm. Pharmacol. 2012, 64, 1510–1521.
  66. Zhang, X.; Zhang, X.; Wang, C.; Li, Y.; Dong, L.; Cui, L.; Wang, L.; Liu, Z.; Qiao, H.; Zhu, C.; et al. Neuroprotection of early and short-time applying berberine in the acute phase of cerebral ischemia: Up-regulated pAkt, pGSK and pCREB, down-regulated NF-κB expression, ameliorated BBB permeability. Brain Res. 2012, 1459, 61–70.
  67. Nam, K.N.; Kim, J.H.; Jung, H.J.; Park, J.-M.; Moon, S.K.; Kim, Y.; Kim, S.Y.; Lee, E.H. Berberine inhibits inflammatory activation of rat brain microglia. Neural Regen. Res. 2010, 5, 1384–1390.
  68. Liu, Y.M.; Niu, L.; Wang, L.L.; Bai, L.; Fang, X.Y.; Li, Y.C.; Yi, L.T. Berberine attenuates depressive-like behaviors by suppressing neuro-inflammation in stressed mice. Brain Res. Bull. 2017, 134, 220–227.
  69. Zhang, Z.; Li, X.; Li, F.; An, L. Berberine alleviates postoperative cognitive dysfunction by suppressing neuroinflammation in aged mice. Int. Immunopharmacol. 2016, 38, 426–433.
  70. Tian, Y.; Zheng, Y.; Wang, Q.; Yan, F.; Tao, Z.; Zhao, F.; Wang, Y.; Huang, Y.; Li, F.; Du, Y.; et al. Berberine Ameliorates Cognitive Impairment by Regulating Microglial Polarization and Increasing Expression of Anti-inflammatory Factors following Permanent Bilateral Common Carotid Artery Occlusion in Rats. CNS Neurol. Disord. Drug Targets 2022, 21, 869–879.
  71. Yoo, K.Y.; Hwang, I.K.; Kim, J.D.; Kang, I.J.; Park, J.; Yi, J.S.; Kim, J.K.; Bae, Y.S.; Won, M.H. Antiinflammatory effect of the ethanol extract of Berberis koreana in a gerbil model of cerebral ischemia/reperfusion. Phytother. Res. PTR 2008, 22, 1527–1532.
  72. Lomphithak, T.; Akara-Amornthum, P.; Murakami, K.; Hashimoto, M.; Usubuchi, H.; Iwabuchi, E.; Unno, M.; Cai, Z.; Sasano, H.; Jitkaew, S. Tumor necroptosis is correlated with a favorable immune cell signature and programmed death-ligand 1 expression in cholangiocarcinoma. Sci. Rep. 2021, 11, 11743.
  73. Xiong, J.; Wang, L.; Fei, X.C.; Jiang, X.F.; Zheng, Z.; Zhao, Y.; Wang, C.F.; Li, B.; Chen, S.J.; Janin, A.; et al. MYC is a positive regulator of choline metabolism and impedes mitophagy-dependent necroptosis in diffuse large B-cell lymphoma. Blood Cancer J. 2017, 7, 8503511.
  74. Liu, L.; Fan, J.; Ai, G.; Liu, J.; Luo, N.; Li, C.; Cheng, Z. Berberine in combination with cisplatin induces necroptosis and apoptosis in ovarian cancer cells. Biol. Res. 2019, 52, 37.
  75. Sengupta, D.; Chowdhury, K.D.; Chatterjee, S.; Sarkar, A.; Paul, S.; Sur, P.K.; Sadhukhan, G.C. Modulation of adenylate cyclase signaling in association with MKK3/6 stabilization under combination of SAC and berberine to reduce HepG2 cell survivability. Apoptosis 2017, 22, 1362–1379.
  76. Ou, X.; Hua, Y.; Liao, X.; Gong, C.; Kang, Y. Cognitive impairments induced by severe acute pancreatitis are attenuated by berberine treatment in rats. Mol. Med. Rep. 2018, 18, 3437–3444.
  77. Chang, C.F.; Lee, Y.C.; Lee, K.H.; Lin, H.C.; Chen, C.L.; Shen, C.J.; Huang, C.C. Therapeutic effect of berberine on TDP-43-related pathogenesis in FTLD and ALS. J. Biomed. Sci. 2016, 23, 72.
  78. Jiang, W.; Wei, W.; Gaertig, M.A.; Li, S.; Li, X.J. Therapeutic Effect of Berberine on Huntington’s Disease Transgenic Mouse Model. PLoS ONE 2015, 10, e0134142.
  79. Huang, M.; Jiang, X.; Liang, Y.; Liu, Q.; Chen, S.; Guo, Y. Berberine improves cognitive impairment by promoting autophagic clearance and inhibiting production of β-amyloid in APP/tau/PS1 mouse model of Alzheimer’s disease. Exp. Gerontol. 2017, 91, 25–33.
  80. Li, S.; Jiang, Y.; Xing, X.; Lin, R.; Li, Q.; Zhou, W.; Qiu, W.; Zheng, W. Protective Mechanism of Berberine on Human Retinal Pigment Epithelial Cells against Apoptosis Induced by Hydrogen Peroxide via the Stimulation of Autophagy. Oxidative Med. Cell. Longev. 2021, 2021, 7654143.
  81. Chen, H.; Ji, Y.; Yan, X.; Su, G.; Chen, L.; Xiao, J. Berberine attenuates apoptosis in rat retinal Müller cells stimulated with high glucose via enhancing autophagy and the AMPK/mTOR signaling. Biomed. Pharmacother. 2018, 108, 1201–1207.
  82. Liu, J.; Liu, P.; Xu, T.; Chen, Z.; Kong, H.; Chu, W.; Wang, Y.; Liu, Y. Berberine Induces Autophagic Cell Death in Acute Lymphoblastic Leukemia by Inactivating AKT/mTORC1 Signaling. Drug Des. Dev. Ther. 2020, 14, 1813–1823.
  83. Zhu, N.; Cao, X.; Hao, P.; Zhang, Y.; Chen, Y.; Zhang, J.; Li, J.; Gao, C.; Li, L. Berberine attenuates mitochondrial dysfunction by inducing autophagic flux in myocardial hypoxia/reoxygenation injury. Cell Stress Chaperones 2020, 25, 417–426.
  84. Li, M.H.; Zhang, Y.J.; Yu, Y.H.; Yang, S.H.; Iqbal, J.; Mi, Q.Y.; Li, B.; Wang, Z.M.; Mao, W.X.; Xie, H.G.; et al. Berberine improves pressure overload-induced cardiac hypertrophy and dysfunction through enhanced autophagy. Eur. J. Pharmacol. 2014, 728, 67–76.
  85. Zhang, Y.J.; Yang, S.H.; Li, M.H.; Iqbal, J.; Bourantas, C.V.; Mi, Q.Y.; Yu, Y.H.; Li, J.J.; Zhao, S.L.; Tian, N.L.; et al. Berberine attenuates adverse left ventricular remodeling and cardiac dysfunction after acute myocardial infarction in rats: Role of autophagy. Clin. Exp. Pharmacol. Physiol. 2014, 41, 995–1002.
  86. Wang, N.; Feng, Y.; Zhu, M.; Tsang, C.M.; Man, K.; Tong, Y.; Tsao, S.W. Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: The cellular mechanism. J. Cell. Biochem. 2010, 111, 1426–1436.
  87. Sun, Y.; Xia, M.; Yan, H.; Han, Y.; Zhang, F.; Hu, Z.; Cui, A.; Ma, F.; Liu, Z.; Gong, Q.; et al. Berberine attenuates hepatic steatosis and enhances energy expenditure in mice by inducing autophagy and fibroblast growth factor 21. Br. J. Pharmacol. 2018, 175, 374–387.
  88. Lin, Y.; Sheng, M.; Weng, Y.; Xu, R.; Lu, N.; Du, H.; Yu, W. Berberine protects against ischemia/reperfusion injury after orthotopic liver transplantation via activating Sirt1/FoxO3α induced autophagy. Biochem. Biophys. Res. Commun. 2017, 483, 885–891.
  89. Hou, Q.; Tang, X.; Liu, H.; Tang, J.; Yang, Y.; Jing, X.; Xiao, Q.; Wang, W.; Gou, X.; Wang, Z. Berberine induces cell death in human hepatoma cells in vitro by downregulating CD147. Cancer Sci. 2011, 102, 1287–1292.
  90. He, Q.; Mei, D.; Sha, S.; Fan, S.; Wang, L.; Dong, M. ERK-dependent mTOR pathway is involved in berberine-induced autophagy in hepatic steatosis. J. Mol. Endocrinol. 2016, 57, 251–260.
  91. Peng, P.L.; Kuo, W.H.; Tseng, H.C.; Chou, F.P. Synergistic tumor-killing effect of radiation and berberine combined treatment in lung cancer: The contribution of autophagic cell death. Int. J. Radiat. Oncol. Biol. Phys. 2008, 70, 529–542.
  92. Chen, P.; Dai, C.H.; Shi, Z.H.; Wang, Y.; Wu, J.N.; Chen, K.; Su, J.Y.; Li, J. Synergistic inhibitory effect of berberine and icotinib on non-small cell lung cancer cells via inducing autophagic cell death and apoptosis. Apoptosis 2021, 26, 639–656.
  93. Chitra, P.; Saiprasad, G.; Manikandan, R.; Sudhandiran, G. Berberine inhibits Smad and non-Smad signaling cascades and enhances autophagy against pulmonary fibrosis. J. Mol. Med. 2015, 93, 1015–1031.
  94. Lopes, T.Z.; de Moraes, F.R.; Tedesco, A.C.; Arni, R.K.; Rahal, P.; Calmon, M.F. Berberine associated photodynamic therapy promotes autophagy and apoptosis via ROS generation in renal carcinoma cells. Biomed. Pharmacother. 2020, 123, 109794.
  95. Zhang, Q.; Wang, X.; Cao, S.; Sun, Y.; He, X.; Jiang, B.; Yu, Y.; Duan, J.; Qiu, F.; Kang, N. Berberine represses human gastric cancer cell growth in vitro and in vivo by inducing cytostatic autophagy via inhibition of MAPK/mTOR/p70S6K and Akt signaling pathways. Biomed. Pharmacother. 2020, 128, 110245.
  96. Han, B.; Wang, K.; Tu, Y.; Tan, L.; He, C. Low-Dose Berberine Attenuates the Anti-Breast Cancer Activity of Chemotherapeutic Agents via Induction of Autophagy and Antioxidation. Dose-Response 2020, 18, 1559325820939751.
  97. Cheng, Z.; Kang, C.; Che, S.; Su, J.; Sun, Q.; Ge, T.; Guo, Y.; Lv, J.; Sun, Z.; Yang, W.; et al. Berberine: A Promising Treatment for Neurodegenerative Diseases. Front. Pharmacol. 2022, 13, 845591.
  98. Zhang, H.; Zhao, C.; Cao, G.; Guo, L.; Zhang, S.; Liang, Y.; Qin, C.; Su, P.; Li, H.; Zhang, W. Berberine modulates amyloid-β peptide generation by activating AMP-activated protein kinase. Neuropharmacology 2017, 125, 408–417.
  99. Zhou, H.; Feng, L.; Xu, F.; Sun, Y.; Ma, Y.; Zhang, X.; Liu, H.; Xu, G.; Wu, X.; Shen, Y.; et al. Berberine inhibits palmitate-induced NLRP3 inflammasome activation by triggering autophagy in macrophages: A new mechanism linking berberine to insulin resistance improvement. Biomed. Pharmacother. 2017, 89, 864–874.
  100. Fan, X.; Wang, J.; Hou, J.; Lin, C.; Bensoussan, A.; Chang, D.; Liu, J.; Wang, B. Berberine alleviates ox-LDL induced inflammatory factors by up-regulation of autophagy via AMPK/mTOR signaling pathway. J. Transl. Med. 2015, 13, 92.
  101. Kline, A.E.; Leary, J.B.; Radabaugh, H.L.; Cheng, J.P.; Bondi, C.O. Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better? Prog. Neurobiol. 2016, 142, 45–67.
  102. Peng, W.H.; Lo, K.L.; Lee, Y.H.; Hung, T.H.; Lin, Y.C. Berberine produces antidepressant-like effects in the forced swim test and in the tail suspension test in mice. Life Sci. 2007, 81, 933–938.
  103. Kuznetsova, L.P.; Sochilina, E.E.; Faddeeva, M.D.; Iagodina, O.V. Effect of some isoquinoline alkaloids on enzymatic activity of acetylcholinesterase and monoamine oxidase. Ukr. Biokhim. Zh. 2005, 77, 147–153.
  104. Ji, H.F.; Shen, L. Molecular basis of inhibitory activities of berberine against pathogenic enzymes in Alzheimer’s disease. Sci. World J. 2012, 2012, 823201.
  105. Ge, P.Y.; Qu, S.Y.; Ni, S.J.; Yao, Z.Y.; Qi, Y.Y.; Zhao, X.; Guo, R.; Yang, N.Y.; Zhang, Q.C.; Zhu, H.X. Berberine ameliorates depression-like behavior in CUMS mice by activating TPH1 and inhibiting IDO1-associated with tryptophan metabolism. Phytother. Res. PTR 2023, 37, 342–357.
  106. Wang, Y.; Tong, Q.; Ma, S.R.; Zhao, Z.X.; Pan, L.B.; Cong, L.; Han, P.; Peng, R.; Yu, H.; Lin, Y.; et al. Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson’s disease by regulating gut microbiota. Signal Transduct. Target. Ther. 2021, 6, 77.
  107. Lee, T.; Heo, H.; Kim Kwon, Y. Effect of Berberine on Cell Survival in the Developing Rat Brain Damaged by MK-801. Exp. Neurobiol. 2010, 19, 140–145.
  108. Lin, T.Y.; Lin, Y.W.; Lu, C.W.; Huang, S.K.; Wang, S.J. Berberine Inhibits the Release of Glutamate in Nerve Terminals from Rat Cerebral Cortex. PLoS ONE 2013, 8, e67215.
  109. Liu, M.; Hurn, P.D.; Alkayed, N.J. Cytochrome P450 in neurological disease. Curr. Drug Metab. 2004, 5, 225–234.
  110. Zhang, P.; Ma, D.; Wang, Y.; Zhang, M.; Qiang, X.; Liao, M.; Liu, X.; Wu, H.; Zhang, Y. Berberine protects liver from ethanol-induced oxidative stress and steatosis in mice. Food Chem. Toxicol. 2014, 74, 225–232.
  111. Zverinsky, I.V.; Zverinskaya, H.G.; Sutsko, I.P.; Telegin, P.G.; Shlyahtun, A.G. Effects of berberine on the recovery of rat liver xenobiotic-metabolizing enzymes after partial hepatectomy. Biomed. Khim. 2015, 61, 381–383.
  112. Zhao, X.; Zhang, J.J.; Wang, X.; Bu, X.Y.; Lou, Y.Q.; Zhang, G.L. Effect of berberine on hepatocyte proliferation, inducible nitric oxide synthase expression, cytochrome P450 2E1 and 1A2 activities in diethylnitrosamine- and phenobarbital-treated rats. Biomed. Pharmacother. 2008, 62, 567–572.
  113. Lee, S.Y.; Jang, H.; Lee, J.Y.; Ma, J.Y.; Oh, S.J.; Kim, S.K. Inhibitory effects of Hwang-Ryun-Hae-Dok-Tang on cytochrome P450 in human liver microsomes. Xenobiotica 2015, 45, 131–138.
  114. Guo, Y.; Pope, C.; Cheng, X.; Zhou, H.; Klaassen, C.D. Dose-response of berberine on hepatic cytochromes P450 mRNA expression and activities in mice. J. Ethnopharmacol. 2011, 138, 111–118.
  115. Guo, Y.; Chen, Y.; Tan, Z.R.; Klaassen, C.D.; Zhou, H.H. Repeated administration of berberine inhibits cytochromes P450 in humans. Eur. J. Clin. Pharmacol. 2012, 68, 213–217.
  116. Cui, H.M.; Zhang, Q.Y.; Wang, J.L.; Chen, J.L.; Zhang, Y.L.; Tong, X.L. In vitro studies of berberine metabolism and its effect of enzyme induction on HepG2 cells. J. Ethnopharmacol. 2014, 158 Pt A, 388–396.
  117. Chatuphonprasert, W.; Nemoto, N.; Sakuma, T.; Jarukamjorn, K. Modulations of cytochrome P450 expression in diabetic mice by berberine. Chem. Biol. Interact. 2012, 196, 23–29.
  118. McDonald, M.G.; Tian, D.D.; Thummel, K.E.; Paine, M.F.; Rettie, A.E. Modulation of Major Human Liver Microsomal Cytochromes P450 by Component Alkaloids of Goldenseal: Time-Dependent Inhibition and Allosteric Effects. Drug Metab. Dispos. Biol. Fate Chem. 2020, 48, 1018–1027.
  119. Wen, C.J.; Wu, L.X.; Fu, L.J.; Shen, D.Y.; Zhang, X.; Zhang, Y.W.; Yu, J.; Zhou, H.H. Preferential induction of CYP1A1 over CYP1B1 in human breast cancer MCF-7 cells after exposure to berberine. Asian Pac. J. Cancer Prev. 2014, 15, 495–499.
  120. Lo, S.N.; Wang, C.W.; Chen, Y.S.; Huang, C.C.; Wu, T.S.; Li, L.A.; Lee, I.J.; Ueng, Y.F. Berberine Activates Aryl Hydrocarbon Receptor but Suppresses CYP1A1 Induction through miR-21-3p Stimulation in MCF-7 Breast Cancer Cells. Molecules 2017, 22, 1847.
  121. Lo, S.N.; Chang, Y.P.; Tsai, K.C.; Chang, C.Y.; Wu, T.S.; Ueng, Y.F. Inhibition of CYP1 by berberine, palmatine, and jatrorrhizine: Selectivity, kinetic characterization, and molecular modeling. Toxicol. Appl. Pharmacol. 2013, 272, 671–680.
  122. Falero-Perez, J.; Song, Y.S.; Sorenson, C.M.; Sheibani, N. CYP1B1: A key regulator of redox homeostasis. Trends Cell Mol. Biol. 2018, 13, 27–45.
  123. Falero-Perez, J.; Sorenson, C.M.; Sheibani, N. Cyp1b1-deficient retinal astrocytes are more proliferative and migratory and are protected from oxidative stress and inflammation. Am. J. Physiol. Cell Physiol. 2019, 316, C767–C781.
  124. Qiu, W.; Jiang, X.H.; Liu, C.X.; Ju, Y.; Jin, J.X. Effect of berberine on the pharmacokinetics of substrates of CYP3A and P-gp. Phytother. Res. PTR 2009, 23, 1553–1558.
  125. Wang, M.; Zhang, J.; Zhao, H.; Wan, D.; Jiang, Z. Berberine combined with cyclosporine A alleviates acute graft-versus-host disease in murine models. Int. Immunopharmacol. 2020, 81, 106205.
  126. Kumar, A.; Ekavali, M.J.; Chopra, K.; Dhull, D.K. Possible role of P-glycoprotein in the neuroprotective mechanism of berberine in intracerebroventricular streptozotocin-induced cognitive dysfunction. Psychopharmacology 2016, 233, 137–152.
  127. Shaker, F.H.; El-Derany, M.O.; Wahdan, S.A.; El-Demerdash, E.; El-Mesallamy, H.O. Berberine ameliorates doxorubicin-induced cognitive impairment (chemobrain) in rats. Life Sci. 2021, 269, 119078.
  128. Ni, S.J.; Yao, Z.Y.; Wei, X.; Heng, X.; Qu, S.Y.; Zhao, X.; Qi, Y.Y.; Ge, P.Y.; Xu, C.P.; Yang, N.Y.; et al. Vagus nerve stimulated by microbiota-derived hydrogen sulfide mediates the regulation of berberine on microglia in transient middle cerebral artery occlusion rats. Phytother. Res. PTR 2022, 36, 2964–2981.
  129. Hong, J.S.; Chu, Y.K.; Lee, H.; Ahn, B.H.; Park, J.H.; Kim, M.J.; Lee, S.; Ryoo, H.S.; Jang, J.H.; Lee, S.R.; et al. Effects of berberine on hippocampal neuronal damage and matrix metalloproteinase-9 activity following transient global cerebral ischemia. J. Neurosci. Res. 2012, 90, 489–497.
  130. Ma, X.; Jiang, Y.; Wu, A.; Chen, X.; Pi, R.; Liu, M.; Liu, Y. Berberine attenuates experimental autoimmune encephalomyelitis in C57 BL/6 mice. PLoS ONE 2010, 5, e13489.
  131. Wu, C.; Yang, K.; Liu, Q.; Wakui, M.; Jin, G.Z.; Zhen, X.; Wu, J. Tetrahydroberberine blocks ATP-sensitive potassium channels in dopamine neurons acutely-dissociated from rat substantia nigra pars compacta. Neuropharmacology 2010, 59, 567–572.
  132. Shigeta, K.; Ootaki, K.; Tatemoto, H.; Nakanishi, T.; Inada, A.; Muto, N. Potentiation of nerve growth factor-induced neurite outgrowth in PC12 cells by a Coptidis Rhizoma extract and protoberberine alkaloids. Biosci. Biotechnol. Biochem. 2002, 66, 2491–2494.
  133. Han, A.M.; Heo, H.; Kwon, Y.K. Berberine promotes axonal regeneration in injured nerves of the peripheral nervous system. J. Med. Food 2012, 15, 413–417.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback