Role of berberine in Alzheimer’s disease

Figures & data

Figure 1 Possible mechanisms by which berberine modifies metabolism of APP.

Notes: In the amyloidogenic pathway, cleavage of APP by β-secretase generates soluble N-terminal fragment (sAPPβ) and C-terminal fragment (C99). C99 can be cleaved by γ-secretase to yield the APP intracellular domain (AICD) and Aβ. In the nonamyloidogenic pathway, α-secretase cleaves APP, generating a soluble fragment of APP (sAPPα) and C-terminal fragment (α-CTF), which is further cleaved by γ-secretase releasing the p3 peptide and AICD. BBR could decrease β-secretase and γ-secretase and inhibit the process of amyloidogenic pathway, lowering the Aβ release and the formation of amyloid plaques. The role of BBR in α-secretase remains unclear in the nonamyloidogenic pathway. ? Represent that the mechanism is unclear.
Abbreviations: BBR, berberine; Aβ, beta-amyloid; AICD, APP intracellular domain; APP, amyloid precursor protein; sAPP, soluble APP.

Table 1 Berberine inhibits oxidative stress in diseases

Diseases	Possible antioxidative mechanism	References
Acute myocardial injury	Inhibiting the activity of LDH, CK, and MDA; declining the activity of SOD and CAT; reducing COX-2 and iNOS expression in I/R myocardium; and increasing HO-1 induction in human aortic endothelial cells	^Citation135
Aging	Reduction of ROS production and oxidative DNA damage; suppressing the level of constitutive mTOR- and DNA damage signaling; and reduction of the level of endogenous oxidants and constitutive DNA damage	^Citation136, ^Citation137
Alzheimer’s disease	Reversing both the increase in malondialdehyde and the decrease in superoxide dismutase activity induced by Calyculin A	^Citation66, ^Citation72, ^Citation91
Atherosclerosis	Reducing oxidative stress and vascular inflammation and suppressing atherogenesis via a mechanism that includes stimulation of AMPK-dependent UCP2 expression	^Citation117
Cancer	Inhibiting reactive oxygen species generation and mitochondrial dysfunction	^Citation138^–^Citation140
Cardiac failure	Downregulating phospholamban and exerting antioxidant activity	^Citation141
Cerebral ischemia diseases	Attenuating ROS production and increasing cell viability, antioxidant defense (GSH and SOD), and oxidant-sensitive proteins (HO-1 and Nrf2)	^Citation77, ^Citation125
Cognitive impairment	Mitigation of the oxidative stress burden	^Citation142, ^Citation109
Diabetes mellitus	The influence on oxidative stress markers (malondialdehyde, urinary 8-hydroxy-2′-deoxyguanosine, superoxide dismutase, aldose reductase, glutathione peroxidase, and total antioxidant capacity) and limiting the inflammatory parameters (vascular adhesion molecule-1, C-reactive protein and high-molecular-weight adiponectin); antioxidative effect via down- and upregulation of GPx and CuZn-SOD expression, respectively; strong potential to improve the oxidant–antioxidant balance; and inhibiting the activation of RhoA/ROCK signaling	^Citation80^–^Citation88, ^Citation143^–^Citation147
Hepatic fibrosis	Decreasing liver malondialdehyde concentration and increasing activities of liver superoxide dismutase, catalase, and glutathione peroxidase	^Citation148
Hepatic injury	Reducing apoptosis, which is possibly involved with the modulation of the PI3K/Akt/mTOR signaling pathway, and modulating antioxidant status and inflammatory cytokines	^Citation149^–^Citation154
Hypertension	Limiting apoptosis and lowering expression of TLR4, Myd88, NF-κB, IL-6, and TNF-α; inhibiting endoplasmic reticulum stress; and subsequently scavenging ROS leading to COX-2 downregulation in carotid arteries	^Citation155, ^Citation156
Ischemic acute renal failure	Via intonation on apoptosis and mitochondrial-dependent pathway in renal ischemia reperfusion-induced mutilation	^Citation157
Kidney damage	The inhibition of oxidative/nitrosative stress, inflammation, autophagy, and apoptosis and the suppression of NF-κB signaling pathway	^Citation157^–^Citation159
Liver disease	Inhibiting mitochondrial dysfunction, oxidative stress, and steatosis and activation of AMP-activated protein kinase	^Citation160^–^Citation162
Metabolic syndrome	Inhibition of mitochondrial function, stimulation of glycolysis, activation of AMPK pathway, suppression of adipogenesis, and induction of LDL receptor expression	^Citation163
Parkinsonism	Neuroprotection in 6-OHDA-induced PD by protecting dopaminergic neurons and reducing the iron accumulation	^Citation164
Retinal degeneration	Diminishing oxidative stress in the retina	^Citation165

Abbreviations: AMPK, adenosine 5′-monophosphate-activated protein kinase; ATF, cAMP-dependent transcription factor; CAT, catalase; CK, creatine phosphokinase; HO-1, heme oxygenase-1; IL, interleukin; LDL, low-density lipoprotein; LDH, lactate dehydrogenase; MCP-1, monocyte chemotactic protein 1; MDA, malondialdehyde; MMP, matrix metalloproteinase; mTOR, mechanistic target of rapamycin; NF-κB, nuclear transcription factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear factor erythroid 2 p45 related factor 2; ROS, reactive oxygen species; SOD, superoxide dismutase; TGF-β, transforming growth factor beta; TLR4, Toll-like receptor 4; TNF-α, tumor necrosis factor-alpha; UCP2, uncoupling protein 2.

Table 2 Berberine retards inflammation in different disorders

Diseases	Possible anti-inflammation mechanism	References
Allergic rhinitis	Reducing allergic inflammation significantly	^Citation166
Alzheimer’s disease	Reversing both the increase in MDA and the decrease in SOD activity induced by Calyculin A	^Citation66, ^Citation72, ^Citation91
Asthma	Inhibiting NF-κB signaling pathway	^Citation167
Atherosclerosis	Reducing oxidative stress and vascular inflammation and suppressing atherogenesis via a mechanism that includes stimulation of AMPK-dependent UCP2 expression	^Citation117, ^Citation168
Cerebral ischemia diseases	Attenuating ROS production and increasing cell viability, antioxidant defense (GSH and SOD), and oxidant-sensitive proteins (HO-1 and Nrf2)	^Citation77, ^Citation125
Colon tumorigenesis	Through AMPK-dependent inhibition of mTOR activity and AMPK-independent inhibition of NF-κB	^Citation169
Diabetes mellitus	Reducing oxidative stress	^Citation20, ^Citation87
Diabetic nephropathy	Inhibiting NF-κB-driven renal inflammation and TGF-β/Smad3 signaling pathway	^Citation170, ^Citation171
Hepatic steatosis and nonalcoholic steatohepatitis	Suppressing endoplasmic reticulum stress	^Citation47, ^Citation172
Hypertension	Limiting expression of TLR4, Myd88, NF-κB, IL-6, and TNF-α	^Citation155, ^Citation156
Irritable bowel syndrome	Reducing oxidative stress and inflammation response	^Citation173
Kidney injury	Suppressing NF-κB signaling pathway	^Citation159
Metabolic syndrome	Inhibition of mitochondrial function, stimulation of glycolysis, activation of AMPK pathway, ATF-2 phosphorylation, and MMP-2 expression; suppression of adipogenesis and induction of LDL receptor expression	^Citation20, ^Citation163, ^Citation174
Mucus hypersecretion	Decreased the release of inflammatory cytokines TNF-α, IL-1β, MCP-1, and inflammatory cells in bronchoalveolar lavage fluid	^Citation175
Myocardial ischemia/reperfusion injury	Reducing oxidative stress and inflammation response	^Citation176, ^Citation177
Obesity	Decreasing proinflammatory cytokines including TNF-α and IL-6	^Citation178
Osteoarthritis	Attenuating IL-1β expression and inhibiting NF-κB signaling pathway	^Citation179
Parkinson’s disease	Reducing oxidative stress	^Citation19
Reflux esophagitis	Improving SOD and HO-1 levels	^Citation180
Retinal diseases	Decreasing oxidative stress and the activation of microglia/macrophages	^Citation165
Steatohepatitis	Against insulin resistance, inflammation, and lipid metabolism	^Citation181
Traumatic brain injury	Limiting the production of inflammatory mediators by glial cells	^Citation182
Ulcerative colitis	Inhibition of NF-κBp65 activation and increase in Nrf2 expression in colorectums	^Citation183

Abbreviations: AMPK, adenosine 5′-monophosphate-activated protein kinase; ATF, cAMP-dependent transcription factor; HO-1, heme oxygenase-1; IL, interleukin; LDL, low-density lipoprotein; LDH, lactate dehydrogenase; MCP-1, monocyte chemotactic protein 1; MDA, malondialdehyde; MMP, matrix metalloproteinase; mTOR, mechanistic target of rapamycin; NF-κB, nuclear transcription factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear factor erythroid 2 p45-related factor 2; ROS, reactive oxygen species; SOD, superoxide dismutase; TGF-β, transforming growth factor beta; TLR4, Toll-like receptor 4; TNF-α, tumor necrosis factor-alpha; UCP2, uncoupling protein 2.

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