Part 1:Huperzine A And Its Neuroprotective Molecular Signaling in Alzheimer’s Disease
Mar 21, 2022
Contact: joanna.jia@wecistanche.com / WhatsApp: 008618081934791
Maria Jesis Friedli 1 and Nibaldo C. Inestrosa1,2,*
1Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes,
Punta Arenas 6210427, Chile; mariajesusfriedli@gmail.com
2Departamento de Biología Celular y Molecular, Centro de Envejecimiento y Regeneración (CARE-UC),
Facultad de Ciencias Biológicas, Pontifificia Universidad Católica de Chile, Santiago 8331150, Chile
*Correspondence: ninestrosa@bio.puc.cl
Abstract: Huperzine A (HupA), an alkaloid found in the club moss Huperzia Serrata, has been used for centuries in Chinese folk medicine to treat dementia. The effects of this alkaloid have been attributed to its ability to inhibit the cholinergic enzyme acetylcholinesterase (AChE), acting as an acetylcholinesterase inhibitor (AChEI). The biological functions of HupA have been studied both in vitro and in vivo, and its role in neuroprotection appears to be a good therapeutic candidate for Alzheimer’s disease (AD). Here, we summarize the neuroprotective effects of HupA on AD, with an emphasis on its interactions with different molecular signaling avenues, such as the Wnt signaling, the pre-and post-synaptic region mechanisms (synaptotagmin, neuroligins), the amyloid precursor protein (APP) processing, the amyloid-β peptide (Aβ) accumulation, and mitochondrial protection. Our goal is to provide an integrated overview of the molecular mechanisms through which HupA affects AD.
Keywords: neurodegenerative diseases; huperzine; AChEI; Alzheimer’s disease; therapeutic potential; neuroinflammation
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1. Introduction
1. Introduction For centuries, Huperzia Serrata has been used in traditional Chinese medicine under the name “Qian Ceng Ta” as a treatment for schizophrenia, inflammation, swelling, poisoning, pain, and memory loss [1–3]. All the properties of H. serrata have been intensively studied in China, and most of the biological activity of H. Serrata appears to be caused by the molecule Huperzine A (HupA). HupA is an unsaturated sesquiterpene alkaloid compound that effectively crosses the blood-brain barrier (BBB), acting as a mixed-competitive, reversible, and selective AChE inhibitor [4–7] with a half-life of 5 h in the bloodstream, reaching a peak concentration at approximately 60 min in humans, and its t 12 has been calculated to be approximately 4–5 h [8]. Its IUPAC name is (1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.02,7] Tribeca-2(7),3,10-tried-5-one. With a molecular weight of 242.32 g/mol [9,10], HupA presents a complex array of structural components: a compact tricyclic structure with a bicyclo [3.1.1] skeleton fused with an α-pyridone ring, an exocyclic ethylidene moiety, and a 3-carbon bridge with an -NH2 group. This complex and unique molecular structure accounts for the interesting biological functions and the high stability of HupA [11], plus it results in the presentation of the correct electrostatic Fifield for binding to AChE [12,13]. The three-dimensional structure of the AChE complexed with the nootropic alkaloid [-]-HupA was resolved at the Weizmann Institute of Science, Israel [14]. Notably, chemically synthesized [−]-HupA inhibits AChE with similar effectiveness as the natural molecule [10], and [+]-Hupa's AChE inhibitor (AChEI) activity is at least 50-fold less potent than that of the naturally occurring stereoisomer [15].
The enzyme AChE catalyzes the hydrolysis of the neurotransmitter acetylcholine into choline and acetic acid, regulating the return of cholinergic neurons to a resting state [16]. Most of the cortical AChE activity present in the brain of AD patients is known to be predominantly associated with the amyloid core of senile plaques [17,18]. The globular tetramer (G4) of AChE present in the central nervous system (CNS) [19] (see Figure 1), forms a stable toxic complex with the amyloid-β (Aβ) peptide during its assembly into Aβ filaments and increases the aggregation and neurotoxicity of amyloid fibrils [20–22].
Figure 1. HupA is an acetylcholinesterase inhibitor (AChEI). HupA has a molecular weight of 242.32 g/mol and acts by inhibiting AChE. In the CNS, AChE is present in a tetrameric form anchored to the membrane, or “Globular Tetramer G4” (G4). HupA is the main biological compound in H. Serrata, which has been used for medicinal purposes in China for centuries. (AChE: acetylcholinesterase; CNS: central nervous system).
The colocalization of AChE activity with the amyloid plaques in the brain is presented in a double transgenic AD model (APPswe/PS1 mice, see below) (see Figure 2). It is interesting to note that HupA has a higher potency and selectivity of inhibition than commonly prescribed AChEIs galantamine, donepezil, tacrine, and rivastigmine both in vitro and in vivo [9,23].
Due to its potent AChEI activity, HupA is used as a treatment for AD. According to the World Health Organization (WHO), 135.5 million people worldwide will be living with dementia by the year 2050. AD accounts for 65% of all dementia cases [24]. It is a progressive neurological degenerative disorder affecting memory, among other cognitive functions [25–27]. Vascular-associated dementia (VaD), on the other hand, is caused by various cerebrovascular diseases, such as cerebral infarction and hemorrhage [28]. These conditions impose great monetary and emotional costs on patients and their caregivers. HupA is approved as the drug of choice for Alzheimer's disease (AD) treatment in China and as a dietary supplement in the United States [29,30], as intake can improve AD pathogenesis [31].
Figure 2. AChE interacts with Aβ in amyloid plaques. Thioflavin-S is used to stain amyloid plaques. Merging the detection of amyloid plaques and of AChE activity confirms colocalization in the brain of an APP/PS1 mouse model of AD (AChE: acetylcholinesterase; APP: Amyloid precursor protein; PS1: presenilin 1).
The biological functions of HupA have been studied both in vitro and in vivo. The present review aims to provide an integrated perspective of the neuroprotective molecular signaling of HupA in dementia, especially in AD.
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2. HupA within the CNS: Modulation of Critical Pathological Conditions
2.1. HupA Mediated Modulation of Amyloid-8 PeptideToxicity
One of the hallmarks of AD is the accumulation of Aβ peptides (both oligomers and fibrils) that associate with AChE to form amyloid plaque, producing neuronal cell death [20,21]. The neuroprotective effect of HupA is in part mediated by a dose-dependent reduction in subcellular amyloid-β accumulation in the cortex and hippocampus as shown in a double transgenic mice model carrying the Swedish-mutant amyloid precursor protein (APP) and deletion in exon 9 of presenilin 1 (PS1) (known as APPswe/PS1 mice) [32], although it is noteworthy that this effect is reportedly absent in TgCRND8 mice [33]. These reductions occur at the protein level through a dose-dependent modulation of the activity of β-site of the APP-cleaving enzyme (BACE1) activity, a reduction in PS1 expression, and a marked increase in a-secretase cleavage, promoting the non-amyloidogenic processing of APP [32,34]. An improvement in the spontaneous working memory of 68% has been observed in APPswe/PS1 mice after HupA treatment, although HupA does not seem to improve cognition in wild-type (WT) mice [35]. In primary cortical neuron cultures, HupA ameliorates oligomeric Aβ42-induced neurotoxicity by reducing the intracellular accumulation of Aβ42 [36].
HupA modulates the activity of glycogen synthase kinase-3β (GSK-3β), a central molecule of wingless-related integration site (Wnt) signaling cascades [32]. GSK-3β is modulated through inhibitory phosphorylation [37], thus stabilizing the levels of β-catenin in the brain [26,34]. HupA treatment concomitantly decreases the levels of hyperphosphorylated tau protein in both the cortex and the hippocampus, indicating that HupA has effects beyond cholinergic modulation.
At the same time, HupA treatment attenuates the Aβ load in brain mitochondrial homogenates and ameliorates the mitochondrial swelling observed in APPswe/PS1 mice, although it has no effect on WT mice [35]. It has been reported that Aβ accumulation causes mitochondrial dysfunction, resulting in neurotoxicity. HupA treatment restores adenosine triphosphate (ATP) levels and reduces reactive oxygen species (ROS) levels increased by Aβ42 in neurons, and prevents Aβ42-mediated destabilization of the mitochondrial membrane [36]. Notably, HupA treatment reduces Aβ42 accumulation in mitochondria-enriched cellular fractions, but has no significant effects on membrane or cytosol Aβ42 levels, indicating that it exerts a specifically mitochondrial effect [36].
HupA also ameliorates Aβ25–35-induced apoptosis. Proteomic analysis showed that HupA downregulates 29 proteins, including the tumor suppressor protein p53, which has a direct link with apoptosis [37]. In a co-culture system of neural stem cells and microglia exposed to Aβ1–42, HupA treatment partially reduced the secretion of inflammatory factors interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein-1α (MIP-1α) [37]. HupA also significantly increases the ratio be- tween B-cell lymphoma-2 (Bcl-2) and Bcl-2-like protein 4 (Bax), resulting in improved cell viability. Similarly, HupA directly acts on microglial cells to reduce the expression of cytokines and chemokines [38]. In primary astrocyte cultures, HupA preincubation reduces Aβ1-42-induced cell damage, preventing peaks in the release of p65 subunit of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) [39].
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2.2. HupA on Dementia
Several studies have evaluated the potential benefits of HupA in human patients. HupA treatment in human subjects suffering from dementia (AD o VaD) shows evidence of improved cognition [4,28,40,41]. It has also been reported that eight weeks of HupA treatment for AD patients improved task switching and alleviated cognitive impairment [42]. The benefits of HupA treatment are apparent when using measurement tools such as Mini-Mental State Exam (MMSE), the AD Assessment Scale-cognitive subscale (ADAS- Cog)) or the ADAS-noncognitive subscale (non-COG) tests. Measuring with tools such as Hasegawa Dementia Scale (HDS) or Wechsler Memory Scale (WMS) tests showed no sig- nificant improvement from HupA treatment [24,25]. These results were corroborated in a randomized clinical trial in which HupA treatment in VaD patients significantly improved cognitive function according to the MMSE and Activities of Daily Living (ADL) tests but not according to the Clinical Dementia Rating (CDR) scores [24,28]. However, other trials conclude that HupA treatment could be more beneficial than psychotherapy and conventional medicine for VaD patients [4]. A small trial testing the effects of HupA tablets in AD patients showed that the intake of 0.2 mg of HupA improved cognition and memory in 58% of patients with no severe side effects [43], and a phase II multicenter, 3-arm randomized, double-blind placebo-controlled trial, evaluated as having high methodological quality in later reviews [4], showed significant cognitive enhancement in patients receiving 0.4 mg of HupA twice a day. Remarkably, this dose was well tolerated for 24 weeks even though most AD patients reported being unable to tolerate currently marketed AChEIs for a long period of time [40,44]. A more recent analysis concludes that HupA improves cognition in AD patients and that its effects are dose and duration-dependent [45].
Some side effects identified in clinical trials are tachycardia, bradycardia, headache, intense dreams, muscle cramps, and arthralgia at high doses. These are well-known cholinergic system-related side effects [8,23]. Nevertheless, these were rated as rare and mild, so HupA remains a well-tolerated drug even in subjects who report intolerance to other AChEIs [4,41]. Some of the described side effects could be mitigated by slow-release formulations or by the synthetic stereoisomer of HupA, which has weaker AChEI activity [11,46].
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