Neuroprotective Herbs for Alzheimer’s Disease

Neuroprotective Herbs for Alzheimer’s Disease: History

Please note this is an old version of this entry, which may differ significantly from the current revision.

Subjects: Neurosciences

Contributor:

Alzheimer’s disease (AD) is a multifactorial, progressive, neurodegenerative disease that is characterized by memory loss, personality changes, and a decline in cognitive function. Medicinal plants and herbal remedies are now gaining more interest as complementary and alternative interventions and are a valuable source for developing drug candidates for AD. Indeed, several scientific studies have described the use of various medicinal plants and their principal phytochemicals for the treatment of AD.

herbs
Alzheimer’s disease
neurodegeneration
ashwagandha
brahmi
cat’s claw
ginkgo biloba
gotu kola
lion’s mane
saffron
shankhpushpi
turmeric
triphala

1. Introduction

Alzheimer’s disease (AD) is one of the most significant global healthcare problems and is now the third leading cause of death in the United States [1,2,3]. While the etiology is incompletely understood, genetic factors account for the 5 to 10% of cases that are familial Alzheimer’s, with the other 90 to 95% being sporadic. Being heterozygous or homozygous for the ApoE ε4 allele significantly increases the risk of developing Alzheimer’s. Efforts to find a cure for AD have so far been disappointing, and the drugs currently available to treat the disease have limited effectiveness, especially if the disease is in its moderate–severe stage.

The underlying pathology is neuronal degeneration and loss of synapses in the hippocampus, cortex, and subcortical structures. This loss results in gross atrophy of the affected regions, resulting in loss of memory, inability to learn new information, mood swings, executive dysfunction, and an inability to complete activities of daily living (ADLs). Patients in the late–severe stage of AD will require comprehensive care owing to complete loss of memory and the disappearance of their sense of time and place. It is believed that therapeutic intervention that could postpone the onset or progression of AD would dramatically reduce the number of cases over the next 50 years [1,2].

The two prominent pathologic hallmarks of Alzheimer’s disease are (a) extracellular accumulation of β-amyloid deposits and (b) intracellular neurofibrillary tangles (NFT). Accumulated Aβ triggers neurodegeneration, resulting in clinical dementia that is characteristic of AD [4,5,6]. However, the poor correlation of amyloid deposits with cognitive decline in the symptomatic phase of dementia may explain why drug targets to β-amyloid have not succeeded to date [5,6].

Intracellular neurofibrillary tangles (NFTs) are commonly seen in AD brains and represent aberrantly folded and hyperphosphorylated isoforms of the microtubule-associated protein tau [7,8]. Studies reveal that the mutated, aberrantly folded, and hyperphosphorylated tau is less efficient in sustaining microtubule growth and function, resulting in the destabilization of the microtubule network—a hallmark of AD [9]. Attention is now on therapies targeted at tau due to failures in β-amyloid clinical drug trials [7,8,10]. However, the recent failure of drugs targeting tau deposits suggests a lack of accurate understanding of the complex pathophysiology of AD [11]. This demonstrates the need to consider other pathophysiological entities underlying AD, including, but not limited to, autophagy, neuroinflammation, oxidative stress, metal ion toxicity, neurotransmitter excitotoxicity, gut dysbiosis, unfolded protein response, cholesterol metabolism, insulin/glucose dysregulation, and infections [12]. In the face of repeated failures of drug therapies targeting amyloid or tau and the large unmet need for safe and effective AD treatments, it is imperative to pursue alternative therapeutic strategies that address all the above-mentioned pathophysiological entities [13,14].

We reported the first examples of reversal of cognitive decline in AD and pre-AD conditions including mild cognitive impairment (MCI) and subjective cognitive impairment (SCI), using a comprehensive, individualized approach that involves determining the potential contributors to the cognitive decline. Some examples of addressing these potential contributors include: (1) identifying gastrointestinal hyperpermeability, repairing the gut, and optimizing the microbiome; (2) identifying insulin resistance and returning insulin sensitivity; (3) reducing protein glycation; (4) identifying and correcting suboptimal levels of nutrients, hormones, and trophic molecules; (5) identifying and treating pathogens such as Borrelia, Babesia, or Herpes family viruses; and (6) identifying and reducing levels of metallotoxins, organic toxins, or biotoxins through detoxification procedures. This sustained effect of the personalized, precision therapeutic program represents an advantage over monotherapeutics [15]. Included in this individualized, precision program are high-quality herbs or their bioactive compounds directed towards the specific needs of each patient as part of the overall protocol, and these have proven to be very effective.

While herbs and herbal remedies have a long history of traditional use and appear to be safe and effective, they have unfortunately received little scientific attention [16,17,18,19,20]. Numerous plants and their constituents are recommended in traditional practices of medicine to enhance cognitive function and to alleviate other symptoms of AD, including poor cognition, memory loss, and depression. A single herb or a mixture of herbs is normally recommended depending upon the complexity of the condition. The rationale is that the bioactive principles present in the herb not only act synergistically but may also modulate the activity of other constituents from the same plant or other plant species [20,21,22]. This approach has been used in Ayurveda, traditional Chinese medicine (TCM), and Native Americans’ system of medicine, where a single herb or a combination of two or more herbs is commonly prescribed for any specific disease [16,17,18,19,23] (Table 1).

Table 1. Neuroprotective herbs for the management of AD have a wide gamut of physiological actions. Listed below are the neurotherapeutic properties of these herbs that ultimately enhance memory and restore normal cognitive functions.

Herb	Study Type	Function/Outcome Measure	Reference
Ashwagandha (Withania somnifera)	in vitro, in vivo, clinical studies	antioxidant, anti-inflammatory, blocks Aβ production, inhibits neural cell death, dendrite extension, neurite outgrowth and restores synaptic function, neural regeneration, reverses mitochondrial dysfunction, improves auditory–verbal working memory, executive function, processing speed, and social cognition in patients	[20,23,24,25,26,27,28,29]
Brahmi (Bacopa monnieri)	in vitro, in vivo, clinical studies	antioxidant, anti-inflammatory, improves memory, attention, executive function, blocks Aβ production, inhibits neural cell death, delays brain aging, improves cardiac function	[30,31,32,33,34,35,36,37]
Cat’s claw (Uncaria tomentosa)	in vitro, in vivo, pre-clinical studies	anti-inflammatory, antioxidant, inhibits plaques and tangles, reduces gliosis, improves memory	[38,39,40,41,42,43,44,45]
Ginkgo biloba	in vitro, pre-clinical, clinical studies	antioxidant, improves mitochondrial function, stimulates cerebral blood flow, blocks neural cell death, stimulates neurogenesis	[46,47,48,49,50]
Gotu kola (Centella asiatica)	in vitro, in vivo, clinical studies	neuroceutical, cogniceutical, reduces oxidative stress, Aβ levels, and apoptosis, promotes dendritic growth and mitochondrial health, improves mood and memory	[51,52,53,54,55,56,57,58]
Lion’s mane (Hericium erinaceus)	in vitro, in vivo, pre-clinical and clinical studies	neuroprotective, improves cognition, anti-inflammatory, blocks Aβ production, stimulates neurotransmission and neurite outgrowth	[59,60,61,62,63]
Saffron (Crocus sativus)	in vitro, in vivo, clinical studies	antioxidant, anti-amyloidogenic, anti-inflammatory, antidepressant, immunomodulation, neuroprotection	[64,65,66]
Shankhpushpi (Convolvulus pluricaulis)	in vitro, in vivo, pre-clinical studies	promotes cognitive function, slows brain aging, antioxidant, anti-inflammatory	[33,36,67,68,69,70].
Triphala (Emblica officinalis, Terminalia bellerica, and Terminalia chebula)	in vitro, in vivo, pre-clinical and clinical studies	antioxidant, anti-inflammatory, immunomodulation, prevents dental caries, antibacterial, antiparasitic, reverses metabolic disturbances	[71,72,73,74,75,76].
Turmeric (Curcuma longa)	in vitro, in vivo, pre-clinical and clinical studies	antioxidant, anti-inflammatory, antimicrobial, blocks Aβ production, inhibits neural cell death	[77,78,79,80,81,82,83,84,85].

Herb

Study Type

Function/Outcome Measure

Reference

Ashwagandha

(Withania somnifera)

in vitro, in vivo,

clinical studies

antioxidant, anti-inflammatory, blocks Aβ production, inhibits neural cell death, dendrite extension, neurite outgrowth and restores synaptic function, neural regeneration, reverses mitochondrial dysfunction, improves auditory–verbal working memory, executive function, processing speed, and social cognition in patients

[20,23,24,25,26,27,28,29]

Brahmi

(Bacopa monnieri)

in vitro, in vivo,

clinical studies

antioxidant, anti-inflammatory, improves memory, attention, executive function, blocks Aβ production, inhibits neural cell death, delays brain aging, improves cardiac function

[30,31,32,33,34,35,36,37]

Cat’s claw

(Uncaria tomentosa)

in vitro, in vivo,

pre-clinical

studies

anti-inflammatory, antioxidant, inhibits plaques and tangles,

reduces gliosis, improves memory

[38,39,40,41,42,43,44,45]

Ginkgo biloba

in vitro, pre-clinical,

clinical studies

antioxidant, improves mitochondrial function, stimulates cerebral blood flow, blocks neural cell death, stimulates neurogenesis

[46,47,48,49,50]

Gotu kola

(Centella asiatica)

in vitro, in vivo,

clinical studies

neuroceutical, cogniceutical,

reduces oxidative stress, Aβ levels, and apoptosis, promotes dendritic growth and

mitochondrial health, improves mood and memory

[51,52,53,54,55,56,57,58]

Lion’s mane

(Hericium erinaceus)

in vitro, in vivo,

pre-clinical and

clinical studies

neuroprotective, improves cognition, anti-inflammatory, blocks Aβ production, stimulates neurotransmission and neurite outgrowth

[59,60,61,62,63]

Saffron

(Crocus sativus)

in vitro, in vivo,

clinical studies

antioxidant, anti-amyloidogenic,

anti-inflammatory, antidepressant,

immunomodulation,

neuroprotection

[64,65,66]

Shankhpushpi

(Convolvulus pluricaulis)

in vitro, in vivo,

pre-clinical studies

promotes cognitive function,

slows brain aging,

antioxidant, anti-inflammatory

[33,36,67,68,69,70].

Triphala

(Emblica officinalis,

Terminalia bellerica, and Terminalia chebula)

in vitro, in vivo,

pre-clinical and clinical studies

antioxidant, anti-inflammatory, immunomodulation, prevents dental caries, antibacterial,

antiparasitic, reverses metabolic disturbances

[71,72,73,74,75,76].

Turmeric

(Curcuma longa)

in vitro, in vivo,

pre-clinical and clinical studies

antioxidant, anti-inflammatory, antimicrobial, blocks Aβ production, inhibits neural cell death

[77,78,79,80,81,82,83,84,85].

It is hoped that the historical knowledge base of traditional systems of medicine, coupled with combinatorial sciences and high-throughput screening techniques, will improve the ease with which herbal products and formulations can be used in the drug development process to provide new functional leads for AD.

2. Other Medicinal Plants for AD

There are several other medicinal plants that have a role in the prevention or treatment of AD. However, in vitro or in vivo studies pertaining to their role in AD are very limited, the majority of the data are from observational studies, and there are no studies to support their role in preventing dementia. These plants include vacha (Acorus calamus), guduchi (Tinospora cordifolia), guggul (Commiphora wightii), jatamansi (Nardostachys jatamansi), jyotismati (Celastrus paniculatus), rosemary (Rosmarinus officinalis), Green tea (Camellia sinensis), St john’s wort (Hypericum perforatum), sage (Salvia spp), Rhodiola rosea, Moringa oleifera, shilajit, and lemon balm.

3. Administration of Herbs

The biggest challenge to drug delivery into the brain is circumventing the BBB, which prevents the entry of numerous potential therapeutic agents. While oral administration of the herbs is a common route of administration, there are no clear studies to demonstrate whether the herbal components have access to the CNS from the systemic circulation. Intranasal administration (INA) is non-invasive, rapid, bypasses the BBB, and directly targets the CNS [17,167,168,169,170,171]. Using this route of delivery, herbs in the form of dry powders or medicated oils are directly administered. Medicated oils may contain a mix of lipophilic and lipid-soluble molecules to ensure the synergistic interaction between different constituents in the herb. The benefits of INA include minimizing the side effects associated with systemic administration, avoidance of brain injury, and overcoming the need for implanting delivery devices [172]. Using this technique, researchers have treated memory losses in transgenic mouse models of AD [173]. While INA may be of great value, several contradictory findings in research studies limit its clinical value [173,174]. Though an attractive strategy in traditional medicinal systems for CNS conditions, there are not many clinical studies to support the use of INS for herbal delivery.

Another method of herbal administration involves the application of a medicated oil on the body and massaging the areas with gentle or deep hand movements. Massage reduces the levels of stress-related hormones and also triggers rapid cerebral blood flow [17,175,176,177,178]. Yet another mode of administration is a transcranial application of medicated oils so that the herbal extracts in the oil are in contact with the cranium or the frontal regions of the brain [17,179,180]. Recent studies point to the role of the endothelial cells lining the CNS capillaries in facilitating the entry of the solutes from the oil into the frontal lobe and prefrontal cortex [17,179,180,181].

This entry is adapted from the peer-reviewed paper 10.3390/biom11040543

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