Molecular Neurobiology (2019) 56:4925–4944 https://doi.org/10.1007/s12035-018-1420-2 Nootropic and Anti-Alzheimer’s Actions of Medicinal Plants: Molecular Insight into Therapeutic Potential to Alleviate Alzheimer’s Neuropathology Md. Sahab Uddin1 & Abdullah Al Mamun1 & Md. Tanvir Kabir 2 & Md. Jakaria3 & Bijo Mathew4 & George E. Barreto5,6 & Ghulam Md Ashraf7 Received: 5 September 2018 /Accepted: 29 October 2018 /Published online: 9 November 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Medicinal plants are the backbone of modern medicine. In recent times, there is a great urge to discover nootropic medicinal plants to reverse cognitive dysfunction owing to their less adverse effects. Alzheimer’s disease (AD) is an age-related neurode- generative disorder characterized by the inevitable loss of cognitive function, memory and language impairment, and behavioral disturbances, which turn into gradually more severe. Alzheimer’s has no current cure, but symptomatic treatments are available and research continues. The number of patients suffering from AD continues to rise and today, there is a worldwide effort under study to find better ways to alleviate Alzheimer’s pathogenesis. In this review, the nootropic and anti-Alzheimer’spotentialsof6 medicinal plants (i.e., Centella asiatica, Clitoria ternatea, Crocus sativus, Terminalia chebula, Withania somnifera,and Asparagus racemosus) were explored through literature review. This appraisal focused on available information about neuro- protective and anti-Alzheimer’s use of these plants and their respective bioactive compounds/metabolites and associated effects in animal models and consequences of its use in human as well as proposed molecular mechanisms. This review progresses our existing knowledge to reveal the promising linkage of traditional medicine to halt AD pathogenesis. This analysis also avowed a new insight to search the promising anti-Alzheimer’sdrugs. Keywords Medicinal plants . Nootropics . Cognitive enhancers . Alzheimer’sdisease . Senile plaques . Neurofibrillary tangles Abdullah Al Mamun and Md. Tanvir Kabir contributed equally to this Introduction work. Alzheimer’s disease (AD) is a progressive, irreversible neuro- * Md. Sahab Uddin [email protected]; [email protected] degenerative disorder that principally influences the older peo- ple and is believed to be accountable for most of the dementia * Ghulam Md Ashraf [email protected]; [email protected] casesinpeopleaged65orolder[1, 2]. The neuropathological hallmarks of AD include deposits of extracellular amyloid β 1 Department of Pharmacy, Southeast University, Dhaka, Bangladesh (Aβ) in the form of senile plaques (SPs) and formation of 2 Department of Pharmacy, BRAC University, Dhaka, Bangladesh intracellular abnormal tau protein as neurofibrillary tangles (NFTs) [3, 4]. In the USA, AD is presently graded as the sixth 3 Department of Applied Life Science, Konkuk University, Chungju, Republic of Korea dominant reason of death; however, current statistics specify that the disorder may position third, immediately after heart 4 Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of disease and cancer, as a leading reason of dying for older Pharmacy, Palakkad, India humans [5]. Considering the recent evidence, in the USA, near- 5 Departamento de Nutrición y Bioquímica, Facultad de Ciencias, ly 5.5 million people are living with AD dementia, among them Pontificia Universidad Javeriana, Bogotá, DC, Colombia 5.3 million people aged 65 and older and about 200,000 people ’ 6 Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, are below age 65 and feature younger-onset Alzheimer s[6]. Santiago, Chile The morphological changes of brain-related with typical 7 King Fahd Medical Research Center, King Abdulaziz University, aging differ from those that happen with AD [7]. Amid the Jeddah, Saudi Arabia most remarkable is the aggregation of Aβ and tau 4926 Mol Neurobiol (2019) 56:4925–4944 hyperphosphorylation in Alzheimer’s brain [8, 9]. Studies lignans that demonstrate diverse pharmacological activities, suggest that each of these is responsible for the disease pro- such as anti-cholinesterase, anti-Alzheimer, anti-amyloidogenic, cess; however, the actual series of events is still obscure [10, hypolipidemic, antioxidant, and anti-inflammatory effects [31]. 11]. As the disease advances, nerve cells in the brain become Therefore, the purpose of the present review is to provide an damaged to a greater extent [12] and this damage ends in the ample precise analysis of various studies on medicinal plants signs and symptoms of AD. One of the most familiar early (Centella asiatica, Clitoria ternatea, Crocus sativus, Terminalia symptoms is trouble in remembering the latest events (i.e., chebula, Withania somnifera,andAsparagus racemosus)that short-term memory loss) [13]. Subsequently, as the disease revealed auspicious nootropic effects and promising against AD progresses symptoms can incorporate difficulty with lan- pathogenesis. guage, disorientation, alterations in mood and personality, poor judgment and decision making, loss of motivation, and behavioral issues [14, 15]. As the condition aggravates, people Materials and Methods with AD regularly draw away from the circle of relatives and society [16] and progressively, bodily capabilities are Search Strategy misplaced that lead to death [17]. Until now, researchers do not absolutely recognize what The available information about traditional nootropic and anti- causes AD in the majority of the population [18]. Alzheimer’s actions of the medicinal plants was collected Approximately 70% of the risk is thought to be genetic with from various electronic sources like PubMed, EBSCO, and a lot of genes typically concerned [19, 20]. Diverse risk factors other databases. Furthermore, available books were also used. comprise a history of head injuries, high blood pressure, de- pression or environmental, and way of lifestyle [16]. The dis- Plants Selection ease progression is linked with plaques and tangles inside the brain [21, 22]. AD may vary from individual to individual on Numerous medicinal plants are effective for nootropic and anti- account of the significance of any one of these factors in Alzheimer’s activities. Amid copious plants, 6 promising anti- growing or declining the risk of developing [23]. Alzheimer’s medicinal plants were considered (Table 1). In this InAD,increasedoxidativestress(OS)isproventobea appraisal, well-documented anti-Alzheimer’s medicinal plants distinguished and early characteristic of susceptible neurons like Ginkgo biloba and Bacopa monnieri were exempted. [24]. Increased reactive oxygen species (ROS) levels are con- nected with augmented accumulation of Aβ and development of SPs [25]. Furthermore, it is obvious that OS takes places Results and Discussion before the formation of NFTs and SPs, where each of which can be neuropathological markers of AD. Nevertheless, the Phytopharmakons are attaining the growing importance both as actual mechanisms accountable for this exaggerated effect re- the traditional system of medicine and as modern medicine due main ambiguous [26]. Generally, abnormal function of the to their therapeutic effects. Novel antioxidants can be consid- central cholinergic system leads to cognitive impairment in ered as a safe and effective way of strengthening the body’s AD patients. The change of this acetylcholinesterase (AChE) defense system against free radicals; ultimately, these can also activity is the key hallmark of AD [27]. No treatments can facilitate protection against degenerative nerve diseases like AD stop, cure, slow or reverse its progression, although a few [39]. Here, we represent the potential effects of various medic- may transiently alleviate symptoms [28]. inal plants as therapeutic in Alzheimer’s pathogenesis. Nature has been a great origin of therapeutic agents from the beginning of human civilization and has continued to offer Centella asiatica humankind with novel therapies. In the AD treatment, the use of natural products is a useful way to raise acetylcholine Cognition-Enhancing, Antioxidant, and Anti-Alzheimer’s (ACh) levels essential for memory function [29]. Research Effects on flora with AChE inhibitors activity is presently ongoing, with the intention of inventing novel potent compounds which Centella asiatica (C. asiatica) is quite well-known to have the are more affordable and show less adverse effects than syn- capacity to increase attention span and concentration, re- thetic drugs. Furthermore, chemical components with antiox- vitalize nervous system and the brain and also to combat aging idant activity can be observed in plants at high concentrations [40]. A study found that C. asiatica exhibited antioxidant and and can be used in the prevention of diverse degenerative cognitive-enhancing properties in normal rats. In rats, for diseases [30]. Phytochemical research has proven the exis- 21 days, the effect of an aqueous extract of C. asiatica (i.e., tence of numerous valuable compounds, including alkaloids, 100, 200, and 300 mg/kg) was estimated in OS induced by triterpenes, polyphenols, tannins, sterols, flavonoids, and streptozotocin (STZ) and cognitive impairment [41]. In an Mol Neurobiol (2019) 56:4925–4944 4927 Table 1 The profile of the nootropic and anti-Alzheimer’s medicinal dismutase (SOD), glutathione peroxidase (GPx) and CAT in plants selected in this appraisal