Reducing iron in the brain: a novel pharmacologic mechanism of huperzine A in the treatment of Alzheimer's disease

Huang, Xiaotian; Qian, Zhong‐Ming; He, Xuan; Gong, Qi; Wu, Kaijin; Jiang, Lirong; Lü, Lina; Zhu, Zhou-Jing; Zhang, Haiyan; Yung, Wing‐Ho; Ke, Ya

doi:10.1016/j.neurobiolaging.2013.11.004

Cited by 78 publications

(60 citation statements)

References 39 publications

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“…For example, Crespo et al hypothesize that the aberrant level of systemic iron status observed in AD patients owe much to an iron homeostasis dysregulation and the intracellular iron accumulation result in increased oxidative damage which would contribute to AD [130]. In accordance with this hypothesis, it has been found that huperzine A (an anti-AD drug in China) inhibits the rising level of iron in CNS, as well as the expression of transferrin-receptor 1 and the transferrin-bound iron uptake in cultured neurons [131]. On the other hand, mitochondrial ferritin has been implicated in the protective mechanism of AD [132,133].…”

Section: Picalm and Iron Homeostasis In Admentioning

confidence: 84%

The Role of PICALM in Alzheimer’s Disease

Tan

2014

Mol Neurobiol

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Alzheimer's disease (AD) is a highly heritable disease (with heritability up to 76%) with a complex genetic profile of susceptibility, among which large genome-wide association studies (GWASs) pointed to the phosphatidylinositol-binding clathrin assembly protein (PICALM) gene as a susceptibility locus for late-onset Alzheimer's disease (LOAD) incidence. Here, we summarize the known functions of PICALM and discuss its genetic polymorphisms and their potential physiological effects associated with LOAD. Compelling data indicated that PICALM affects AD risk primarily by modulating production, transportation, and clearance of β-amyloid (Aβ) peptide, but other Aβ-independent pathways are discussed, including tauopathy, synaptic dysfunction, disorganized lipid metabolism, immune disorder, and disrupted iron homeostasis. Finally, given the potential involvement of PICALM in facilitating AD occurrence in multiple ways, it might be possible that targeting PICALM might provide promising and novel avenues for AD therapy.

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Section: Picalm and Iron Homeostasis In Admentioning

confidence: 84%

The Role of PICALM in Alzheimer’s Disease

Tan

2014

Mol Neurobiol

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“…[21][22][23] Studies have shown that HupA exerts multiple neuroprotective effects in addition to inhibition of AChE. [24][25][26][27] HupA has been demonstrated to be clinically useful as a palliative agent for AD in the People's Republic of China and is marketed in the USA as a dietary supplement. 28 However, because of the lack of brain selectivity, commercially available formulations of HupA, such as tablets, capsules, and injections, have serious side effects in gastrointestinal and peripheral cholinergic systems.…”

Section: Introductionmentioning

confidence: 99%

Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer’s disease

Meng¹,

Wang²,

Hua³

et al. 2018

IJN

245

101

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Background Safe and effective delivery of therapeutic drugs to the brain is important for successful therapy of Alzheimer’s disease (AD). Purpose To develop Huperzine A (HupA)-loaded, mucoadhesive and targeted polylactide-co-glycoside (PLGA) nanoparticles (NPs) with surface modification by lactoferrin (Lf)-conjugated N-trimethylated chitosan (TMC) (HupA Lf-TMC NPs) for efficient intranasal delivery of HupA to the brain for AD treatment. Methods HupA Lf-TMC NPs were prepared using the emulsion–solvent evaporation method and optimized using the Box–Behnken design. The particle size, zeta potential, drug entrapment efficiency, adhesion and in vitro release behavior were investigated. The cellular uptake was investigated by fluorescence microscopy and flow cytometry. MTT assay was used to evaluate the cytotoxicity of the NPs. In vivo imaging system was used to investigate brain targeting effect of NPs after intranasal administration. The biodistribution of Hup-A NPs after intranasal administration was determined by liquid chromatography–tandem mass spectrometry. Results Optimized HupA Lf-TMC NPs had a particle size of 153.2±13.7 nm, polydispersity index of 0.229±0.078, zeta potential of +35.6±5.2 mV, drug entrapment efficiency of 73.8%±5.7%, and sustained release in vitro over a 48 h period. Adsorption of mucin onto Lf-TMC NPs was 86.9%±1.8%, which was significantly higher than that onto PLGA NPs (32.1%±2.5%). HupA Lf-TMC NPs showed lower toxicity in the 16HBE cell line compared with HupA solution. Qualitative and quantitative cellular uptake experiments indicated that accumulation of Lf-TMC NPs was higher than nontargeted analogs in 16HBE and SH-SY5Y cells. In vivo imaging results showed that Lf-TMC NPs exhibited a higher fluorescence intensity in the brain and a longer residence time than nontargeted NPs. After intranasal administration, Lf-TMC NPs facilitated the distribution of HupA in the brain, and the values of the drug targeting index in the mouse olfactory bulb, cerebrum (with hippocampus removal), cerebellum, and hippocampus were about 2.0, 1.6, 1.9, and 1.9, respectively. Conclusion Lf-TMC NPs have good sustained-release effect, adhesion and targeting ability, and have a broad application prospect as a nasal drug delivery carrier.

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“…These aberrant changes were significantly and dose-dependently ameliorated by HupA treatment (Figure 2). To our knowledge, this is the first direct evidence regarding the protective effect of HupA against iron overloadinduced injury to neuronal cells, which may shed additional light on the mechanisms underlying the anti-brain damage effects of HupA in animal models involving elevated iron levels in the central nervous system [9,30] . Numerous studies have proven that iron is among the redox-active transition metals that can produce massive amounts of ROS, particularly hydroxyl radicals through the Fenton reaction [37] .…”

Section: Discussionmentioning

confidence: 82%

“…Second, HupA also markedly ameliorates oxidative stress in chronic cerebrally hypoperfused and aged rats [27,28] and attenuates mitochondrial dysfunction in APP/PS1 transgenic mice [29] and rats after intracerebral hemorrhage (ICH) [30] . It has been suggested that ICH causes significant iron overload in the brain [31] , and the levels of brain iron in APP/PS1 transgenic mice are markedly greater than those in aged-matched control mice [9] . Together, the evidence indicates that excessive iron accumulation in neuronal cells is closely associated with massive oxidative damage and mitochondrial dysfunction, which subsequently lead to neurotoxicity [14,32] .…”

Section: Acta Pharmacologica Sinicamentioning

confidence: 99%

“…Abnormally high iron concentrations in the brain have been widely reported in AD patients [7,8] , and the well-known APP/PS1 transgenic mouse AD animal model [9] . Additionally, excess iron has been proven to cause neuronal damage in multiple in vitro and in vivo studies [10][11][12] because excess iron can generate reactive oxygen species (ROS) [13] and is closely associated with mitochondrial dysfunction [14] .…”

Section: Introductionmentioning

confidence: 99%

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Acetylcholinesterase-independent protective effects of huperzine A against iron overload-induced oxidative damage and aberrant iron metabolism signaling in rat cortical neurons

et al. 2016

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Aim: Iron dyshomeostasis is one of the primary causes of neuronal death in Alzheimer's disease (AD). Huperzine A (HupA), a natural inhibitor of acetylcholinesterase (AChE), is a licensed anti-AD drug in China and a nutraceutical in the United Sates. Here, we investigated the protective effects of HupA against iron overload-induced injury in neurons. Methods: Rat cortical neurons were treated with ferric ammonium citrate (FAC), and cell viability was assessed with MTT assays. Reactive oxygen species (ROS) assays and adenosine triphosphate (ATP) assays were performed to assess mitochondrial function. The labile iron pool (LIP) level, cytosolic-aconitase (c-aconitase) activity and iron uptake protein expression were measured to determine iron metabolism changes. The modified Ellman's method was used to evaluate AChE activity. Results: HupA significantly attenuated the iron overload-induced decrease in neuronal cell viability. This neuroprotective effect of HupA occurred concurrently with a decrease in ROS and an increase in ATP. Moreover, HupA treatment significantly blocked the upregulation of the LIP level and other aberrant iron metabolism changes induced by iron overload. Additionally, another specific AChE inhibitor, donepezil (Don), at a concentration that caused AChE inhibition equivalent to that of HupA negatively, influenced the aberrant changes in ROS, ATP or LIP that were induced by excessive iron. Conclusion: We provide the first demonstration of the protective effects of HupA against iron overload-induced neuronal damage. This beneficial role of HupA may be attributed to its attenuation of oxidative stress and mitochondrial dysfunction and elevation of LIP, and these effects are not associated with its AChE-inhibiting effect.

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Reducing iron in the brain: a novel pharmacologic mechanism of huperzine A in the treatment of Alzheimer's disease

Cited by 78 publications

References 39 publications

The Role of PICALM in Alzheimer’s Disease

The Role of PICALM in Alzheimer’s Disease

Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer’s disease

Acetylcholinesterase-independent protective effects of huperzine A against iron overload-induced oxidative damage and aberrant iron metabolism signaling in rat cortical neurons

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Reducing iron in the brain: a novel pharmacologic mechanism of huperzine A in the treatment of Alzheimer's disease

Cited by 78 publications

References 39 publications

The Role of PICALM in Alzheimer’s Disease

The Role of PICALM in Alzheimer’s Disease

Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer&rsquo;s disease

Acetylcholinesterase-independent protective effects of huperzine A against iron overload-induced oxidative damage and aberrant iron metabolism signaling in rat cortical neurons

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Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer’s disease