Molecular Mechanisms of Berberine’s Neuroprotection: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by 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 [38,39,40,41,42,43,44,45,46,47,48,49][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 [38,39,40,41,42,43,44,45,46,47,48,49][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 [50,51,52,53][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 [6,8,14,54,55,56,57,58,59,60,61,62,63,64,65,66,67][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) [68][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 [69][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 [69][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 [55,70][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 [61][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 [71][37].
Mitochondria, being both the main targets and producers of ROS, play a central role in oxidative-stress-related neurodegeneration [72][38]. Studies have demonstrated that ROS production is regulated by various antioxidant defense pathways, including the PI3K/Akt pathway, Nrf2 pathway, and PPAR pathway [24,73,74][39][40][41]. Nrf2, a key regulator of antioxidant defense, transcriptionally controls the expression of numerous protective genes in response to oxidative stress [75][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 [75][42]. Many studies have reported that the Nrf2–antioxidant response element axis is a critical target against oxidative stress in neurodegenerative diseases [76][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 [24][39]. Activation of the Akt signaling pathway by BBR inhibits ROS production, protecting against oxidative stress induced by various agents [77,78][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 [66][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 [79][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 [80][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) [74][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 [81][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]) [82][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 [83][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 [84][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 [85][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 [18][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 [35,87,88,89][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 [35,87,88,89][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 [35,87,88,89][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 [23,90,91,92,93][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 [94][63]. Furthermore, BBR partially ameliorates cognitive dysfunction induced by lipopolysaccharide (LPS) by attenuating neuroinflammation [95][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 [96][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 [97][66]. BBR supplementation could reduce TLR4/MyD88/NF-κB signaling transduction and attenuate neuronal death induced by microglial-conditioned media [92][61]. BBR effectively inhibits the inflammatory activation of rat brain microglia by inactivating the NF-κB/iNOS/NO pathway or activating the AMPK pathway [90,98,99][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 [99,100,101,102][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 [103][72]. Previous studies have indicated that BBR may act as a necroptosis inducer in cancer cells, showcasing potential anti-tumor effects [104,105,106][73][74][75]. BBR usually plays a neuroprotective role in the treatments for neurological diseases and neuronal cells inhibiting necroptosis [107][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 [107][76].

3. Induction of Autophagy

Berberine (BBR) exhibits neuroprotective qualities by inducing autophagy and facilitating the clearance of toxic aggregate proteins [108,109,110][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 [111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127][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 [9,109][78][97]. This process ultimately alleviates motor dysfunction and extends the survival period in a mouse model of Huntington’s disease [109][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 [110][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 [128][98]. Interestingly, a great many studies have indicated that autophagy is AMPK-dependent or triggered via the AMPK/mTOR pathway [4,129][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 [130][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 [131,132][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 [133,134][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 [131][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 [37][106]. BBR administration has also been shown to suppress cholinesterase activity, thereby protecting the cholinergic system, and enhancing memory function in diabetic rats [67,133][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 [135][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 [136][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 [137][109]. It has been reported that BBR has a potent regulatory effect on CYP450 activities in liver, heart, kidney, and breast tissues [7,138,139,140,141,142,143,144,145,146,147][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 [148][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 [149][122]. It has been demonstrated that the deficiency of CYP1B1 could protect retinal astrocytes against oxidative stress and inflammation [150][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 [142,151][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 [152][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 [153][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 [26][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 [154][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 [155][129]. These functions also contribute to the therapeutic effects of BBR against multiple sclerosis disease [156][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 [157][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 [79,158,159][46][132][133].

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