Keywords

1 Introduction

Neurological diseases are increasingly recognized as major causes of death and disability worldwide. The most prevalent neurological diseases are Parkinson’s (PD), multiple sclerosis (MS), AD, and Huntington’s disease (HD). The most important pathological symptoms of neuro degenerative diseases are mitochondrial dysfunction, synapse loss, elevated oxidative stress, protein abnormalities, decreased neuronal survival, and nitrosative stress (Winner et al. 2011). It is accepted that among neurodiseases, AD is most complex neurological disease characterized by gradual dementia and failure of cognitive function. The prevalence of AD accounts for about 60% of all cases (van Marum 2008). As per World Alzheimer Report (2015), 46.8 million individuals have mental illness and the number will increase twofold every 20 years. The disorder is typified by variations in different genes, such as the β amyloid precursor protein (APP) and persenilins (PS1, PS2), proteins such as BACE (Aβ cleaving enzyme), APOE, PS1/2, and APP, tau and secretases play a crucial role in the immunopathology of AD.

The approved medicine used to treat cognitive impairment in AD patients are tacrine, donepezil, rivastigmine, galantamine, and memantine. They improve overall memory temporarily, but cause gastrointestinal complexity, such as diarrhea, hepatotoxicity, nausea, weight loss, etc. (Kim et al. 2010). Herbal recipes used in traditional medicinal systems are fundamentally preventive, protective, nutritive, and curative. These traditional herbs have been used to treat progression of disorders of neurons like abstraction and AD since years ago. Because these traditional herbs and isolated chemical components may be less toxic than synthetic drugs. The herbal drugs used in medicinal systems of Indian tradition to cure AD are Centella asiatica (Apiaceae), Bacopa monnierii (Scrophulariaceae), Curcuma longa (Zingiberaceae), Withania somnifera (Solanaceae), Celastrus paniculatus (Celastraceae), Nardostachys jatamansi (Caprifoliaceae), Tinospora cordifolia (Menispermaceae), Morinda citrifolia (Rubiaceae), etc. Natural compounds such as alkaloids, terpenoids, and phenolic components of plant origin have been proved to have the potential therapeutic value to prevent AD because of their inflammation/oxidative stress reducing capacity and anti-amyloidogenic properties (Kim et al. 2010).

The present work is concentrated on the role of the potential traditional herbal extracts and their active principles in the prevention of AD with special reference to non-phenolic compounds of the herbal drugs to understand its possible mechanism.

1.1 Bacopa monnieri (L.) Wettst.

B. monnieri (L.) Wettst. (Family: Scrophulariaceae) is known as Brahmi (Telugu) or Aindri (Sanskrit). Medhya rasayana is a popular brain tonic prescribed by Ayurveda practitioners for intellectual, cognition rejuvenation and in memory loss conditions (Vishnupriya and Padma 2017). Studies on standardized extract of B. monnieri revealed that the extract significantly reversed scopolamine induced impaired the acquisition and recapture of memory producing both retrograde and anterograde amnesia in Morris water maze mice model (Saraf et al. 2011). Further, Holcomb et al. (2006) evaluated the efficacy of B. monnieri extract on expression studies of M146L presenilin-1 mutations and Swedish amyloid precursor protein in PSAPP mice. The results showed that B. monnieri extract has downregulated amyloid (Abeta) gene expression 60% and reversed behavioral changes in incessant locomotion and Y-maze performance in PSAPP mice. Bacosides (Fig. 16.1), isolated from B. monnieri, significantly reduced stress in adult male Sprague Dawley rats via modulating the expression levels of Hsp 70 and activities of superoxide dismutase and cytochrome P450 (Chaudhari et al. 2017).

Fig. 16.1
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Bacoside structure

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B. monnieri extract significantly decreased glutamate- and β-amyloid protein (25–35) challenged toxicity in cortical neurons by reducing intracellular oxidative stress and by inhibiting lipid peroxidation in neuronal cells (Limpeanchob et al. 2008). Amyloid-beta (Aβ42) polypeptide plays remarkable role in AD development due to neuronal dysfunction. Bacoside A, saponin isolated from B. monnieri significantly reduced toxicity of cells and suppressed fibril formation both in membrane vesicles and in buffer solution (Malishev et al. 2017). Methanolic extract of B. monnieri significantly inhibited S-nitroso-N-acetyl-penicillamine (SNAP) induced generation of free radical and damage of DNA in concentration-dependent manner in isolated rat astrocytes (Russo et al. 2003). In a double-blind placebo and randomized experiment, BacoMind, a standardized phytochemical enriched B. monnieri extract, improved cognitive functions such as attentiveness and remembrance in patients (Barbhaiya et al. 2008), in AD patients (Goswami et al. 2011) and in medical students (Kumar et al. 2016).

Further, Usha et al. (2008) conducted a clinical experiment on efficiency of BacoMind on cognitive enhancement in children. The results showed that BacoMind at 225 mg/day for a span of 4 months, significantly increased working memory and short-term verbal memory in 28 children volunteers. Rai et al. (2015) evaluated protective effect of CDRI-08, a special extract of B. monnieri in scopolamine-induced neurotoxicity amnesic mice. In results, pretreatment of CDRI-08 to amnesic mice treated with scopolamine bring back the spatial memory. The mechanism of action the drug found to be enhancing the expression levels of GluN2B subunit and decreased levels of acetylcholinesterase activity prefrontal cortex and hippocampus, similar to the normal mice. Oral administration of Medhya Rasayana, an Ayurvedic drug prepared from B. monnieri significantly reduced anticholinesterase activity and secured the cholinergic neurons than the standard drugs rivastigmine, donepezil, and galantamine. It further reduced the deposition levels of β-amyloid proteins in hippocampal and stress-induced damages in hippocampal regions of rat models in in vivo study (Chowdhuri et al. 2002). Peth-Nui et al. (2012) investigated the effect of standardized B. monnieri extract on brain function and remembrance in 23 males and 37 female healthy elders for a period of 12 weeks and concluded that the B. monnieri extract improved attention, cognitive processing, and working memory partly by inhibiting the activity of acetyl cholinesterase (AChE) activity.

1.2 Boswellia serrata Roxb.

B. serrata Roxb. (Family: Burseraceae) is known as olibanum or Indian Frankincense. Its oleo gum resin is traditionally used in Indian traditional systems (Ayurveda or Unani or ethnomedicine) to treat several types of human ailments like pain and cardiac debility, inflammatory health ailments, blood disorders, rheumatism, urinary disorders, and corneal ulcer (Paranjpe 2001; Khan 1885). Nrf2, a transcription factor, plays a main role in regulation of antioxidant genes/proteins such as heme oxygenase-1 (HO-1). Dysregulation of HO-1 is connected to pathogenesis of variety of neurodegenerative diseases including AD (Habtemariam 2019). Medication with acetyl-11-keto-β- boswellic acid (AKBA, Fig. 16.2) resulted noteworthy reduction in the volume of infarcts and number of apoptotic cells and upregulated expression amounts of HO-1 and Nrf2 in brain tissues of tested animals.

Fig. 16.2
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Acetyl-11-keto-β- boswellic acid structure

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Further, AKBA increased the expression of HO-1 and Nrf2 expression in oxygen and glucose deprivation induced oxidative stress in primary cultured neurons (Ding et al. 2014). In another experiment, B. serrata at 50 mg/kg significantly improved memory retrieval and step-through latency in streptozotocin-induced Alzheimer disease in rat models (Zaker et al. 2015). Medication with water extract of B. serrata gum resin for 42 days of experimental schedule, significantly decreased streptozotocin-induced Alzheimer disease symptoms, i.e., decreased step-through latency, increased the decimal of step-through into the dark compartment and increased the spending time in the dark compartment (Beheshti and Aghaie 2016).

1.3 Coffea arabica L.

Methylxanthines isolated from the coffee (Coffea arabica L. and C. canephora L.) reported to have antagonists on adenosine-receptors. Caffeine (Fig. 16.3) a indifferent, competitive inhibitor of A2A and A1 receptors of adenosine, diffused in CNS. General depressant reaction is due to binding of adenosine to specific targets, lowering blood pressure and slowing rate of hart beat (Gu et al. 1992). As per epidemiological reports, caffein and A2A receptor inhibitor contribute a crucial role in delaying and avoidance of the emergence of AD. Maia and de Mendonca (2002) case study results demonstrated that people consumed two cups of coffee per day for 20 years have low risk for onset of AD than the people consumed less coffee. Systematic review on case control and prospective studies on efficiency of coffee on AD, concluded that coffee has therapeutic effects (Barranco Quintana et al. 2007). These consequences were in line with previous reports in which consumption of coffee was regularly protective against PD for women and men without estrogen therapy (Ascherio et al. 2001, 2004; Ascherio and Chen 2003).

Fig. 16.3
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Structure of caffeine

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1.4 Galanthus nivalis L.

G. nivalis L. (Family: Amaryllidaceae) known as snowdrop, is widely grown in gardens and naturalized particularly in northern Europe. The active principle isolated from this plant is an alkaloid, galantamine. Galantamine is commercially accepted as AChEi drug to treat AD patients at different stages in many countries. Castillo (2017) assessed the efficiency of galantamine on beta-amyloid peptide-challenged damage of DNA and cell viability in SH-SY5Y neuroblastoma cell lines of human in vitro studies. The results revealed that treatment with galantamine exhibited noteworthy recovery of cell longevity, reduced the death of necrotic cells and exerted anticancer effects. Lopes et al. (2013) assessed the neuroprotective activity of galantamine alone or in mixed with memantine, an N-methyl-d-aspartate (NMDA) receptor inhibitor, in rat primary cultures of cortical neurons. Galantamine exhibited its neuroprotective effect via activation of α7 and α4b2 nicotinic acetylcholine receptor at a concentration of 5 μ mol/L.

Prins et al. (2014) conducted a clinical, placebo-controlled, randomized, double-blind trial experiment to investigate the neuroprotective effect of galantamine in 364 mild cognitive impairment patients for a time schedule of 1 year at 16–24 mg flexible-dose every day. They concluded that patients received galantamine showed a lower rate of whole brain atrophy than patients received placebo. In another experiment, galantamine significantly attenuated β-amyloid1–40 and thagapsigarin challenged cell toxicity of SH-SY5Y cell lines and bovine chromaffin cell. The mechanism related to neuroprotective effect of galantamine was by activation of levels of α7 nicotinic receptors and enhancing the expression levels of Bcl-2, the antiapoptotic protein (Arias et al. 2004). In in vitro study, galantamine significantly modulated regulation of signal transmission via intracellular cascade implicated in rat hippocampal slices of brain ischemia-reperfusion model put through glucose and oxygen deprivation (OGD) subsequently reoxygenation. Galantamine expressed its neuroprotective mechanism by reducing the induction of iNOS and secretion of NO caused by OGD via Jak2. It also decreased ROS generation by NADPH oxidase (NOX) activation (Egea et al. 2012). Kihara et al. (2004) investigated the efficiency of galantamine on β-amyloid-increased glutamate toxicity using cortical neurons of primary rat cultures. The defensive effect of galantamine was expressed by partial inhibition of α7 nAChR antagonists.

1.5 Ginkgo biloba L.

G. biloba L. (Family: Ginkgoaceae), known as the maidenhair tree or Ginkgo, belongs to Gymnosperms. The usage of Ginkgo biloba L. to treat neuro diseases was started by German physicians in 1965. EGb 761, a patented and commercialized extract of G. biloba leaves was developed in the early 1970s (Wagner 1999). The standardized products of Ginkgo extensively prescribed in Europe and the USA to treat various types of neurodegenerative diseases. EGb 761 extracts rich in flavonoids and terpenic lactones may be responsible for its therapeutic action. The terpenoid fraction consists mainly diterpenic lactones, sesquiterpene trilactone, the bilobalide, and the ginkgolides A, B, C, J and M (Birks and Grimley 2009).

G. biloba extract and active ingredient ginkgolide B (GB), a terpene trilactone solution reduced the endothelial permeability coefficients and upregulated ZO-1 and occludin expression, the tight junction proteins in endothelial cells (Fang et al. 2010). Administration of ginkgolide B demonstrated that GB reduced the neurological deficits core and enhanced the amount of nestin, mRNA expression levels of neurotrophic factor derived from the brain and growth factor of the epidermis. Further, it enhanced brain-derived neurotrophic factors expression levels in animal models with middle cerebral artery occlusion (MCAO) (Zheng et al. 2018). Further, ginkgolide B derivative, 10-O-(N, N, dimethyl aminoethyl)-ginkgolide B methane sulfonate, (XQ-1H) significantly reduced high lipid profile, cerebral infarct size and improved Blood–Brain Barrier (BBB) permeability in hyperlipidemic rats (Fang et al. 2015). Pretreatment with ginkgolide K (GK) reduced mitochondrial fission, modulated mitochondrial dysfunction and inhibited mitochondrial permeability transition pore opening through a GSK-3β-dependent mechanism of action in both MCAO mice and OGD/R neuroblastoma cells (Zhou et al. 2017).

EGb 761 and its component, ginkgolide A, modulated Aβ-induced disease symptoms such as reduced chemotaxis behavior, 5-HT hypersensitivity and paralysis in a transgenic Caenorhabditis elegans (Wu et al. 2006). In in vitro study, ginkgolide B attenuated pro-oxidant Aβ25–35 peptide induced oxidative stress symptoms such as higher amount of ROS/RNS and decreased concentration of mitochondrial Apurinic/apyrimidinic endonuclease 1 (APE1) in human neuroblastoma SH-SY5Y and IMR-32 cells (Kaur et al. 2015). Bilobalide, diterpene constituent of G. biloba, showed neuroprotection in ischemia-induced neurotoxicity in mice model. The mechanism involves drug reversed ischemia-induced brain damage, mitochondrial dysfunction, leading to reduction in the release of glutamate amount (Schwarzkopf et al. 2013).

1.6 Hedera colchica (K. Koch) K. Koch

H. colchica (K. Koch) K. Koch (Family: Araliaceae) commonly called ivy/Persian ivy, is an evergreen woody vine, native to Turkey. Hederacolchiside E, saponin, active principle isolated from H. colchica reported to have antioxidant activity (Gülçin et al. 2004). Neuroprotective efficiency of hederacolchiside E, isolated by bioactivity-guided fractionation from root extract of Pulsatilla koreana, was studied in in vivo and in vitro methods (Han et al. 2007). Hederacolchiside E reversed scopolamine-challenged cognitive impairment in rats and reduced amyloid-beta peptide (1–42) induced cell toxicity in human SK-N-SH cells. Hederacolchiside E and its 11 derivative compounds were assessed for neuroprotective effects against H2O2- and Aβ1–42-induced neurotoxicity using cell-based assays (Li et al. 2018). Compound 1 and 7 exhibited noteworthy reduction in LDH release levels, amount of intracellular ROS, and extent of malondialdehyde (MDA) enhancement in Aβ1–42-induced cells.

1.7 Huperzia serrata (Thunb. ex Murray) Trevis.

H. serrata (Family: Lycopodiaceae) known as the club moss, has been used by tribes of China to treat strain, swellings, contusion, and schizophrenia. Liu et al. (1986) isolated active chemical constituent, the alkaloid (−)-huperzine A, reported to possess AChE inhibition, which was associated with the traditional uses of this plant.

Huperzine A significantly modulated the D-galactose (D-gal) induced neurodegenerative disease symptoms such as increased cellular senescence and auditory brainstem response (ABR) threshold and reduced neurofilament in the cochlear tissues in Sprague Dawley rats. Further it also suppressed expression levels of NF-kB in Schwann cells and notably blocked D-gal-stimulated expression amounts of pro-inflammatory markers such as IL-1b, IL-6 and TNF-α (Li and Shi 2019). Huperzine A attenuated beta-amyloid protein, H2O2, ischemia, glutamate, and staurosporine-induced cell toxicity and programmed cell death in animal models. The protective mechanism of Huperzine A involved in restoring the oxidative stress controls the expression levels of apoptotic markers i.e., Bcl-2, caspase-3, P53, and Bax, mitochondrial protection and interferes with APP metabolism (Wang and Tang 2005).

In in vivo study, Huperzine A exhibited noteworthy reduction in pathological symptoms, i.e., memory deficiency and neurodegeneration, induced by Aβ1–40 in both hippocampus and cortex of animal models, and inhibited amyloid deposits formation in cortex (Wang et al. 2001). Additionally, huperzine A also reported that it can directly process the amyloid precursor protein (Peng et al. 2006). With regard to cell culture studies, treatment with (-)-huperzine increased the secretion levels of α-APPs, and inhibited Aβ in embryonic kidney 293 cells of human, transfected with the Swedish mutation (Peng et al. 2006, 2007). Acetylcholinesterase (AChE) inhibitory potential and attenuation of Aβ-induced toxicity in NG108-15 and PC cells were studied (Zhang et al. 2002).

Receptors of glutamate play crucial role in the alteration of synaptic plasticity and play noteworthy roles in learning and memory (Contractor and Heinemann 2002). Cells treated with huperzine-A (100 nM) significantly modulated the glutamate (100 μM) induced morphological changes, such as reduction of axon-like processes and diffusion of cell aggregates and cell viability of cell cultures of rat cerebellum (Ved et al. 1997). Huperzine A at 10 μM concentration attenuated N-methyl-d-aspartate (NMDA) challenged cell viability in neuronal cultures in concentration-dependent manner. The binding capacity of huperzine A to proximal to the phencyclidine binding sites and MK-801 is the diagnostic feature in the process of NMDA receptor modulating activity (Gordon et al. 2001). Neuroprotective effect of huperzine A and enantiomers of huperzine A demonstrated by inhibiting the MK-801 binding capacity in the cerebral cortex of animal models was studied (Zhang et al. 2000). Huperzine A was identified as an efficient drug in pre- and post-treatment experiments, against N-methyl-d-aspartate induced seizures and epilepsy (Coleman et al. 2008).

In a placebo-controlled, double-blind, parallel, multi-centered clinical experiment, it showed noteworthy developments in behavior, cognition and daily living activities than patients given with placebo was studied in China (Xu et al. 1995, 1999; Zhang et al. 2002a). Similarly, the efficiency of huperzine-A on learning and memory enhancement clinical experiment in school students with 34 pairs was studied in double-blind method in China (Sun et al. 1999). They conclude that huperzine A-treated students group showed better performance in Chinese-language lesson quizzes than the placebo-treated group. A multi-centered, randomized, prospective, double-blind, three-arm, dose-escalation clinical experiment was conducted to assess the neuroprotective effect of huperzine A in 210 patients with AD in the USA. Patients treated with 400 μg of huperzine A demonstrated a 2.27-point enhancement in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale, while 0.29- point decline was observed in the after 11 weeks treatment period (Rafii et al. 2011).

1.8 Withania somnifera Dunal.

W. somnifera Dunal. (Family: Solanaceae) is locally called as Aswagandha (Sankskrit). In Ayurveda, the root of Ashwagandha has been used as a Rasayana and it is used as stimulant, diuretic, tonic, aphrodisiac, narcotic, astringent, and thermogenic (Singh et al. 2011). W. somnifera root extract showed a noteworthy improvement in the gripping ability, motor movement patterns and restored tyrosine hydroxylase and antioxidant enzyme activity in paraquat (PQ) and maneb challenged nigrostriatal dopaminergic neurodegeneration in mice models (Prakash et al. 2013). Withanolide-A (Fig. 16.4), a major chemical constituent of W. somnifera root showed neuroprotective ability by modulating brain damage, morphology of brain tissue, levels of neurotransmitter in cerebral and brain tissue morphology in mice (Mukherjee et al. 2020). Banu et al. (2019) investigated the neuroprotective efficiency of withaniferin-A, steroidal lactone characterized from roots of W. somnifera on aging induced oxidative stress in substantia nigra (SN) and striatum (ST) of aged rat brain. In conclusion, withaniferin-A significantly modulated the aging induced oxidative stress biochemical changes such as reduced motor activity, increased free radical concentration, reduced antioxidant enzyme levels, increased active caspase-3 activity, enhanced apoptotic nuclear morphology in striatum and substantia nigra of aged rat. Further, Rabhi et al. (2019) studied the neuroprotective activity of CR-777, a glutathione derivative of withaferin A (Fig. 16.5), neurotoxicity caused by 6-hydroxydopamine (6-OHDA), α-synuclein (α-Syn) and 1-methyl-4-phenylpyridinium (MPP+), in rat dopaminergic neuron cells. In 6-OHDA-treated neurons, CR-777 at nanomolar concentrations enhanced neurite network and cell survival and reduced the expression levels of α-Syn in rat dopaminergic neurons.

Fig. 16.4
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Withanolide-A structure

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Fig. 16.5
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Withaniferin-A structure

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2 Perspectives

Medicinal plants used in traditional medicinal systems have been used in the prevention of neurological diseases since long time. Natural compounds isolated from plant sources such as terpenoids, alkaloids, and phenolic components have been reported to have the potential therapeutic value to prevent AD because of their anti-amyloid genic, reduction capacity of oxidative stress and inflammation properties. Some of the potential medicinal plant extracts and its chemical constituents scientifically proved its intellectual, cognition rejuvenation and memory enhancing power in AD patients, such as Bacopa monnieri extract and its active principle bacoside A, ginkgolides from Ginkgo biloba, withanolides and withaniferin from Withania somnifera, huperzine from Huperzia serrata, etc. Extensive research studies are to be conducted in order to establish the long-term usage and efficacy of using phytochemicals as potential therapeutics for neurological diseases and sustainable utilization of drug yielding plants by using biotechnological interventions.