Plant-Derived Bioactive Compounds in the Management of Neurodegenerative Disorders: Challenges, Future Directions and Molecular Mechanisms Involved in Neuroprotection

Neurodegenerative disorders encompass a wide range of pathological conditions caused by progressive damage to the neuronal cells and nervous-system connections, which primarily target neuronal dysfunction and result in problems with mobility, cognition, coordination, sensation, and strength. Molecular insights have revealed that stress-related biochemical alterations such as abnormal protein aggregation, extensive generation of reactive oxygen and nitrogen species, mitochondrial dysfunction, and neuroinflammation may lead to damage to neuronal cells. Currently, no neurodegenerative disease is curable, and the available standard therapies can only provide symptomatic treatment and delay the progression of the disease. Interestingly, plant-derived bioactive compounds have drawn considerable attention due to their well-established medicinal properties, including anti-apoptotic, antioxidant, anti-inflammatory, anticancer, and antimicrobial properties, as well as neuroprotective, hepatoprotective, cardioprotective, and other health benefits. Plant-derived bioactive compounds have received far more attention in recent decades than synthetic bioactive compounds in the treatment of many diseases, including neurodegeneration. By selecting suitable plant-derived bioactive compounds and/or plant formulations, we can fine tune the standard therapies because the therapeutic efficacy of the drugs is greatly enhanced by combinations. A plethora of in vitro and in vivo studies have demonstrated plant-derived bioactive compounds’ immense potential, as proven by their capacity to influence the expression and activity of numerous proteins implicated in oxidative stress, neuroinflammation, apoptosis, and aggregation. Thus, this review mostly focuses on the antioxidant, anti-inflammatory, anti-aggregation, anti-cholinesterase, and anti-apoptotic properties of several plant formulations and plant-derived bioactive compounds and their molecular mechanisms against neurodegenerative disorders.


Introduction
Globally, neurodegenerative disorders affect millions of people, imposing psychological and socio-economic burdens on the population, and epidemiological data indicate that nearly one in six of the world population suffer from neurodegenerative disorders. Dementia, in general, refers to a set of symptoms that impact a person's memory, reasoning, and social abilities. Neurodegenerative diseases such as Alzheimer's disease (AD), vascular dementia (VD), Lewy body dementia (LBD), frontotemporal dementia (FtD), and mixed dementia (MD) are known as progressive dementias, whereas Parkinson's disease (PD), Huntington's disease (HD), and traumatic brain injury (TBI) are linked to dementia. Dementia is prominently demarked by cognitive changes such as memory loss, disorientation, confusion, and difficulty with communication, coordination, organization, and motor functions, as well as psychological changes including depression, anxiety, paranoia, inappropriate behavior, and personality changes [1]. Current data on neurodegenerative diseases suggest that the world population may face greater risk of being affected by many neurodegenerative disorders in future. Late-onset-dementia prevalence estimates are rising exponentially with age, and epidemiological studies suggest that 45 million individuals have late-onset dementia, whereas young-onset-dementia prevalence estimates vary from 42.3 to 54 per 100,000 people [2]. Several factors contribute to dementia, including age and family history [3], alcohol and smoking [4], nutrition, physical activity and lifestyle [5], sleep disturbances [6], diabetes [7], cardiovascular health [8], and environmental risk factors [9]. Often, the majority of neurodegenerative diseases are strongly linked with aging, sharing aging-related biological hallmarks such as deregulated mitochondrial signaling, epigenetic modulations, genomic instability, cellular senescence, altered cell-to-cell communication, telomere shortening, and deregulated nutrient sensing [10]. Diagnosing dementia is a challenging task; biomarker-based diagnosis may provide accuracy but no single test is sufficient to diagnose dementia. Therefore, cognitive neuropsychological tests, brain (CT, MRI, and PET) scans, laboratory tests, and neurological and psychiatric evaluation may help in diagnosing dementias [11,12].

Plants and Their Bioactive Compounds in Averting the Pathogenesis of Neurodegenerative Disorders
Unfortunately, most dementias are not curable, but symptomatic treatment can be achieved by medications (cholinesterase inhibitors), occupational therapies, alternative medicines, and other methods. For example, donepezil, rivastigmine, and galantamine are prescribed to treat Alzheimer's disease, as well as for vascular dementia, Lewy body dementia, and Parkinson's disease [13]. Moreover, in recent decades, plants and their bioactive compounds have gained tremendous attention due to their excellent health benefits. A growing body of studies on plants and their bioactive compounds clearly suggests that they exert a number of biological actions, including neuroprotection [14], cardioprotection and
Shikonin administration by gavage to the rat model of vascular dementia at a dose of 10 mg/kg/day resulted in improved morphological changes in the CA1 region of the hippocampal neurons by down-regulating the expression of p-Akt, p-PTEN, p-CREB, and BDNF. Subsequently, shikonin was also reported to attenuate apoptosis induction by alleviated expression of bcl-2 and reduced bax expression in a dose-dependent manner [62]. Ursolic acid has long been studied for its neuroprotective properties against a myriad of neurodegenerative illnesses, such as chemical-induced cognitive loss and neurotoxicity, traumatic brain damage, cerebral ischemia and reperfusion injury, and subarachnoid hemorrhage. Mechanistic insights indicate that ursolic acid elevated the expression of FoxO1, Akt, Nrf2, SOD, GPx, CAT, and GR while down-regulating expression of TLR4, ICAM-1, IL-1β, TNF-α, NF-κB P65, IL-6, iNOS, and MMP-9, which augmented antioxidation, apoptosis inhibition, and inflammation attenuation. In a recent study, rosmarinic acid and ursolic acid were demonstrated to exert protective effects by improving spatial and recognition memory as well as anxiety in Aβ 1-42 -induced BALB/c mice [63]. Gastrodin, a bioactive phytochemical from Gastrodia elata, has been shown to effectively treat epilepsy, dizziness, dementia, and ischemic stroke. In an in vivo study, oral intake of gastrodin reduced apoptosis by modifying the expression of MAPK, bax, and bcl-2, and reduced autophagy by influencing the expression of beclin-1, p62, and LC3-II. Gastrodin reduced beta-amyloid (Aβ 1-40/42 ) accumulation and alleviated cognitive impairment caused by bilateral common carotid-artery occlusion (BCCAO), as well as hippocampal CA1 and CA3 pyramidal neuronal damage in vascular dementia [64]. Another study indicated that gastrodin treatment suppressed ferroptosis induction and improved learning ability and memory impairment in rats with vascular dementia and the basis for the neuroprotective effects was suggested as gastrodindecreased levels of Fe 2+ and MDA and elevated GSH content by upregulation of Nrf2 and GPx4 and down-regulated Cox2 and kelch-like ECH-associated protein (Keap1) [65]. Quercetin induced reversal of memory impairment by alleviating the activity of IL-6 and TNF-α, suppressing Scopolamine-induced cell death, and degeneration in hippocampal sub-regions and prefrontal cortex in the brain of AD-model mice [66]. Figure 1 shows the role of phytochemicals in the suppression of apoptosis induction. effectively treat epilepsy, dizziness, dementia, and ischemic stroke. In an in vivo study, oral intake of gastrodin reduced apoptosis by modifying the expression of MAPK, bax, and bcl-2, and reduced autophagy by influencing the expression of beclin-1, p62, and LC3-II. Gastrodin reduced beta-amyloid (Aβ1-40/42) accumulation and alleviated cognitive impairment caused by bilateral common carotid-artery occlusion (BCCAO), as well as hippocampal CA1 and CA3 pyramidal neuronal damage in vascular dementia [64]. Another study indicated that gastrodin treatment suppressed ferroptosis induction and improved learning ability and memory impairment in rats with vascular dementia,andthe basis for the neuroprotective effects was suggested as gastrodin-decreased levels of Fe2+ and MDA and elevated GSH content by upregulation of Nrf2 and GPx4 and down-regulated Cox2 and kelch-like ECH-associated protein (Keap1) [65]. Quercetin induced reversal of memory impairment by alleviating the activity of IL-6 and TNF-α, suppressing Scopolamine-induced cell death, and degeneration in hippocampal sub-regions and prefrontal cortex in the brain of AD-model mice [66]. Figure 1 shows the role of phytochemicals in the suppression of apoptosis induction. Figure 1. Apoptosis is triggered through the activation of intrinsic as well as extrinsic pathways involving modulation of several pro-and anti-apoptotic proteins. Phytochemicals can up-regulate anti-apoptotic proteins such as Bcl-2 while down-regulating expression of pro-apoptotic proteins, including bax, cytochrome-c, caspase-9, and caspase-3, in neurodegenerative diseases. Phytochemicals also enhance the expression of pro-survival-related proteins as well as Nrf-2, which leads to antioxidant response. Apoptosis is triggered through the activation of intrinsic as well as extrinsic pathways involving modulation of several pro-and anti-apoptotic proteins. Phytochemicals can up-regulate anti-apoptotic proteins such as Bcl-2 while down-regulating expression of pro-apoptotic proteins, including bax, cytochrome-c, caspase-9, and caspase-3, in neurodegenerative diseases. Phytochemicals also enhance the expression of pro-survival-related proteins as well as Nrf-2, which leads to antioxidant response. Ampelopsin A, a common bioactive component of Vitis vinifera, was shown to restore Scopolamine-induced long-term potentiation impairment in hippocampal CA1 and CA3 synapses in C57BL/6 mice, which was achieved by modulating BDNF/CREB signaling pathways; thereby, ampelopsin A exhibited neuroprotective and neurocognitive effects [67]. Centella asiatica is the main source of asiaticoside, which showed significant improvement in altered behavior and impairment in vascular dementia. Additionally, asiaticoside was found to be associated with the mitigation of hippocampal-tissue damage and formation of autophagosomes through increasing the expression of beclin-1 and microtubule-associated protein light chain 3 (LC3)-II and decreased phosphorylation of mTOR in rats [68]. Rosiridin, a natural monoterpene produced in Rhodiola rosea, has been demonstrated to affect oxidative stress and neuroinflammatory markers in rats by exhibiting anti-AChE activity and restoring normal levels of GSH, MDA, SOD, IL-6, IL-1, TNF-, caspase-3/-9, and IFN-γ [69]. A recent study found that methanolic, aqueous, and chloroform extracts of Glaucium corniculatum have neuroprotective properties against hydrogen peroxide-induced neuronal injury in PC12 cells. Several alkaloids were reported to be in all three solvents, and the antioxidant and anti-apoptotic effects of chloroform-alkaloid extract were linked to the inhibition of intracellular ROS formation and the alleviation of expression of bax and caspase-3/-9, respectively [70]. Another study examined the possible neuroprotective effects of rehmannioside A (isolated from Rehmanniae Radix) against vascular dementia. The mechanistic insights revealed that reduced oxidative stress, inflammation, and apoptosis induction were due to rehmannioside A-mediated activation of Nrf2 and attenuated expression of caspase-3 and NF-κB in a mouse model of vascular dementia [71]. In a study using a mouse model of vascular dementia, rats were administered 50 and 100 mg/kg Panax ginseng extract for eight weeks, leading to significant improvement in behavioral function and augmented neuronal density, which possibly occurred in response to elevated expression of VEGF and (FGF) [72].
Dracocephalum moldavica (L.) is a rich source of tilianin, and investigations on tilianin have shown its anti-apoptotic, anti-neurodegenerative, and antioxidant benefits, as well as improved cognitive impairment, which were attributed to restoration of ERK1/2 and CREB signaling and impeding JNK-, MAPK-, p38-, and NF-κB-related inflammatory responses in rats with vascular dementia [73]. Kaempferol, which was isolated from the leaves of Mespilus germanica (L.), has been studied for its potential role in Alzheimer's disease, together with its impact on oxidative stress, neuroinflammation, apoptosis, lipid peroxidation, and cognitive impairment in an ovariectomized rat model of sporadic Alzheimer's disease. They observed that kaempferol increased spatial learning and memory, increased antioxidant status by increasing GSH and SOD levels, and lowered tumor necrosis factor-α activity and malondialdehyde levels in the rats' brains [74]. Marinoid J, a phenylethanoid, is a key phytoconstituent of Avicennia marina, and showed neuroprotective effects by reducing MDA levels and NO activity while augmenting glutathione-peroxidase content in the tissues of the hippocampal region and ameliorating cognitive impairment in vascular dementia [75]. Morin, a polyphenolic compound, is isolated from the members of the Moraceae family and has long been widely exploited for its range of biological actions, including neuroprotection, antioxidation, anti-aggregation, and anti-inflammation abilities. One such study has shown that morin and MK-801 combination treatments abated expression of dementia-related proteins, including Aβ 42 , APO-E, tau, and β-catenin phosphorylation, and exerted anti-inflammatory actions by altering the activity of IL-6, TNF-α, caspase-3, and NF-κB. Furthermore, it was demonstrated that morin and MK-801 combined post-treatment resulted in behavioral improvements; altered apoptosis, autophagy, and inflammatory responses; and conferred neuroprotective benefits in a rat model of mild repeated traumatic brain injury [76]. A recent study delved into whether Perilla frutescens leaf extract may improve vascular dementia. In all of these experiments, extracts at concentrations of 30, 60, and 90 mg/kg were orally administered perioperatively for 23 days, resulting in reversal of IL-6, TNF-α, and NO, as well as NF-κB, MAPK, and iNOS activities after a 12 h pretreatment with extract in lipopolysaccharide-induced neuroinflammation in rats [77]. Another recent finding on the neuroprotective effects of Salvia macilenta on Aβinjected male albino Wistar rats found that a 50 mg/kg/day oral dosage of Salvia macilenta for 10 days reduced apoptosis, raised GSH and Nrf2 levels, and decreased TNF-α and IL-6 levels in the hippocampus and prefrontal cortex [78]. The studies explored whether glycyrrhizic acid protects against cognitive impairment in chronic cerebral hypoperfusion, attempting to find whether it would have potent enzymatic and non-enzymatic antioxidant activity by fixing intracellular ROS generation, as well as inhibiting cytochrome-c release to prevent apoptosis induction. Finally, it was shown that glycyrrhizic-acid treatment led to improvement of pyramidal neurons, myelin, and dendritic-spine density in a mouse model of vascular dementia [79].

Exploring Anti-Amyloid β (Aβ) Activity of Plants and Their Bioactive Compounds in Neurodegenerative Disorders
Alzheimer's disease is mainly characterized by the deposition of oligomeric assemblies of amyloid β-protein (AβO), which leads to neurotoxicity and aggravates tau abnormalities, oxidative stress, and synaptic disturbances. For these reasons, numerous phytoconstituents have been investigated for their neuroprotective effects, as depicted in Figure 2. Tyrosol and hydroxytyrosol from olive oils inhibited AβO-dependent caspase-3 activation, whereas tyrosol did not affect AβO aggregation [80]. Interestingly, another study suggested that oral administration of hydroxytyrosol led to attenuation of spatio-cognitive deficits and AβO-induced deregulation of JAK2/STAT3, PI3K/Akt, ERK-MAPK, and JNK-p38 signaling were reversed by the compound [81]. Several researchers showed that honokiol exhibited neuroprotective effects, as honokiol administered intraperitoneally up to 14 days resulted in improvement in spatial-learning impairments in a dose-dependent manner and suppressed apoptosis and neuronal damage in the CA1 region of the hippocampus, and another study also presented honokiol as an anti-apoptotic agent because it suppressed AβO-induced apoptosis through inhibition of ROS production and attenuation of NF-κB signaling pathway in AβO-treated neurons [82]. Oral administration of ferrulic acid was demonstrated to reduce AβO deposition in the cerebral region, and ferrulic acid diminished cognitive impairment in a mouse model, whereas antioxidant effects of ferrulic acid against AβO were attributed to the activation of Nrf2 via ERK1/2 pathway [83,84]. Other investigators have reported ferrulic acid to be neuroprotective against Aβ 42 -induced neurotoxicity and oxidative stress in rat primary cortical neurons, whereas another found ferulic acid to be anti-apoptotic against AβO-induced cell death in neuroblastoma cells [85,86]. In a rat model of permanent bilateral common carotid-artery-occlusion (2VO)-induced vascular dementia, gastrodin was indicated to ameliorate memory impairment and executive dysfunction. The study also showed that gastrodin, at a dosage of 90 mg/kg/day, could decrease the formation of Aβ 1-40 and Aβ 1-42 plaques in the plasma and hippocampus of 2-VO rats by reducing tau and Aβ phosphorylation [87]. Naringenin, a common flavanone, is widely distributed in many citrus fruits, showing neuroprotective effects against Aβ 1-42 evoked neurotoxicity by restoring AMPK levels and abating Aβ concentration in neuronal cells of mice, and displayed autophagy-inductive ability by alleviating beclin-1 ATG5 and ATG7 in Neuro2a cells and primary mouse neurons [88].
A novel sesquiterpenoid, Pocahemiketone A from Pogostemon cablin, was shown to alleviate NLR -family pyrin domain-containing 3 (NLRP3) inflammasome-dependent pyroptosis and oxidative stress, suggesting neuroprotective effects against Aβ 25-35 -mediated damage in SH-SY5Y cells [89]. Myricetin and dihydromyricetin, flavonoids present in many fruits and vegetables, have been shown to have an array of biological effects, such as antioxidant, anti-neuroinflammation, and inhibitory efficacy against Aβ oligomers in AD. Myricetin treatment resulted in the suppression of Fe 2+ -induced cell death in SH-SY5Y cells and showed anti-AChE activity and reversed Scopolamine-induced cognitive deficits in a mouse model [90]. Sulforaphane, an isothiocyanate found in cruciferous vegetables, was studied for its neuroprotective properties in a mouse model with AD lesions caused by a combination of D-galactose and aluminum. Further investigations of sulforaphane by these researchers showed amelioration of spatial cognitive impairment and attenuation of Aβ plaques in the cerebral cortex and hippocampal regions of sulforaphane-administered AD-lesion mice, whereas the mechanistic insights revealed that sulforaphane elevated glutathione peroxidase RNA expression and prevented Aβ deposition and peroxidation in mice with Alzheimer-like lesions [91]. Ethanolic extract of the leaves of Elaeagnus glabra f. oxyphylla decreased the formation of Aβ plaques at an IC 50 value of 32.01 µg/mL and attenuated oxidative stress at an IC 50 value of 12.32 µg/mL in AD. They also identified 16phytocompounds, with procyanidin B3, procyanidin B4, and helichrysoside exerting substantial anti-Aβ aggregation effects at IC 50 values of 14.59, 32.64, and 44.45 µM, respectively [92]. Recently, rosmarinic acid in Salvia fruticosa was shown to have inhibitory action against Aβ 1-42 -induced cytotoxicity on SH-SY5Y cells by down-regulating glycogen synthase kinase (GSK) 3β and β-secretase activation at IC 50 values of 6.52 ± 1.14 and 86 ± 2.9 µg/mL, respectively [93]. Another study showed that oral administration of extract of qingyangshen (Chinese herbal medicine) ameliorated learning ability and spatial memory. The researchers suggested that neuroprotective effects occurred in response to the inhibition of astrocytosis, microgliosis, and aggregation of Aβ and tau proteins while augmenting poly-ADP ribose polymerase (PARP) expression in the brains of transgenic mice [94]. Oxidative stress due to the production of reactive oxygen species may lead to neurodegeneration. Activated microglia and reactive astrocyte generate ROS, pro-inflammatory cytokines, and inducible nitric-oxide synthase (iNOS), which may cause further damage. Binding of TNF-α to its receptor can lead to the activation of many signaling pathways, which may cause apoptosis induction and inflammation. On the other hand, phytochemicals have great ability to target apoptosis, inflammation, and oxidative stress, as depicted in the figure.
A novel sesquiterpenoid, Pocahemiketone A from Pogostemon cablin, was shown to alleviate NLR -family pyrin domain-containing 3 (NLRP3) inflammasome-dependent pyroptosis and oxidative stress, suggesting neuroprotective effects against Aβ25-35-mediated damage in SH-SY5Y cells [89]. Myricetin and dihydromyricetin, flavonoids present in many fruits and vegetables, have been shown to have an array of biological effects, such as antioxidant, anti-neuroinflammation, and inhibitory efficacy against Aβ oligomers in AD. Myricetin treatment resulted in the suppression of Fe 2+ -induced cell death in SH-SY5Y cells and showed anti-AChE activity and reversed Scopolamine-induced cognitive deficits in a mouse model [90]. Sulforaphane, an isothiocyanate found in cruciferous vegetables, was studied for its neuroprotective properties in a mouse model with AD lesions caused by a combination of D-galactose and aluminum. Further investigations of sulforaphane by these researchers showed amelioration of spatial cognitive impairment and attenuation of Aβ plaques in the cerebral cortex and hippocampal regions of sulforaphane-administered AD-lesion mice, whereas the mechanistic insights revealed that sulforaphane elevated glutathione peroxidase RNA expression and prevented Aβ deposition and peroxidation in mice with Alzheimer-like lesions [91]. Ethanolic extract of the leaves of Elaeagnus glabra f. oxyphylla decreased the formation of Aβ plaques at an IC50 value of 32.01 μg/mL and attenuated oxidative stress at an IC50 value of 12.32 μg/mL in AD. They also identified 16phytocompounds, with procyanidin B3, procyanidin B4, and helichrysoside exerting substantial anti-Aβ aggregation effects at IC50 values of 14.59, 32.64, and 44.45 μM, respectively [92]. Recently, rosmarinic acid in Salvia fruticosa was shown to have inhibitory action against Aβ1-42-induced cytotoxicity on SH-SY5Y cells by down-regulating glycogen synthase kinase (GSK) 3β and β-secretase activation at IC50 values of 6.52 ± 1.14 and 86 ± 2.9 μg/mL, respectively [93]. Another Oxidative stress due to the production of reactive oxygen species may lead to neurodegeneration. Activated microglia and reactive astrocyte generate ROS, pro-inflammatory cytokines, and inducible nitric-oxide synthase (iNOS), which may cause further damage. Binding of TNF-α to its receptor can lead to the activation of many signaling pathways, which may cause apoptosis induction and inflammation. On the other hand, phytochemicals have great ability to target apoptosis, inflammation, and oxidative stress, as depicted in the figure.
Several triterpene saponins were isolated from the methanolic extract of Stenocereus pruinosus, and thioflavin-T assay revealed the significant inhibitory power of triterpenes against Aβ aggregation [95]. Various flavonoids, isoflavonoids, and coumestan are widely distributed in Pueraria lobata. In a recent study, coumestrol, an active phytoconstituent of Pueraria lobata leaves, displayed anti-Aβ aggregation and selective inhibition of monoamine-oxidase activation at an IC 50 1.99 ± 0.68 µM, suggesting neuroprotective effects of the active compound against AD [96]. Ginsenoside F1, an active component in Panax ginseng, was studied for its neuroprotective properties, together with its ability to reduce amyloid beta aggregation in Alzheimer's disease. Ginsenoside F1 at 2.5 µM inhibited Aβ aggregation in SH-SY5Y neuronal cells in an in vitro study. Besides that, after two hours of post-treatment, ginsenoside F1 was found to be capable of crossing the blood-brain barrier, with elevated levels of insulin-degrading enzyme and neprilysin proteins after eight weeks of administration of 10 mg/kg/d ginsenoside F1 and reduced Aβ plaques in mice models of Alzheimer's disease (AD) [97]. Pandanus amaryllifolius has wide distribution in Southeast Asia and is exploited for its health-benefit effects, including vitamins, antioxidants, and anti-diabetic and anticancer properties. Notably, crude-alcoholic extract and crude-base extract of Pandanus amaryllifolius in doses of 50 µg/mL led to obstructed Aβ oligomerization and deposition, increased cell survival, suppression of ROS generation, and restored mitochondrial functions at different doses in SY-SY5Y cells [98].
Carthamus tinctorius (L.) and Taraxacum coreanum are common traditional remedies in Asian nations, and their antioxidant and anti-inflammatory properties have been studied. Carthamus tinctorius (L.) seeds and Taraxacum coreanum were shown in a recent study to improve cognitive dysfunction, learning, and memory abilities synergistically when compared to a single therapy. Interestingly, both plants suppressed the production of amyloidogenesis-associated proteins such as β-secretase and γ-secretase in Aβ 25-35 -infused rats [99]. Interestingly, terpenes such as β-caryophyllene and α-bisabolol at a dose up to 100 µM showed significant antioxidant activity and enhanced cell survival against Aβ exposure, and inhibited Aβ 1-42 fibril formation and deposition [100]. Cirsium japonicum var. maackii is a medicinal herbal plant with antibacterial and anti-inflammatory properties. In a recent study, an ethyl-acetate fraction from the plant demonstrated neuroprotective effects, evidenced by improved spatial memory and object recognition in comparison to the untreated group. They also demonstrated a dose-dependent reduction in lipid peroxidation and NO generation, resulting in better cognitive impairment and antioxidant status in Aβ 25-35 -induced rats [101]. Of note, curcumin and resveratrol treatment showed decreased oxidative stress by inhibiting ROS generation, suppressed hyperphosphorylation of tau protein at threonine (T) 181 and T205, and protected SH-SY5Y cells from AβO damage [102].    Neuroprotection by abrogating apoptosis through increased expression of bcl-2 and TrkB and suppression of bax and caspase-3 [55] Sinensetin

Citrus plants In vivo (mice)
Inhibited cell death and degeneration by down-regulation of IL-6 and TNF-α [66] Asiaticoside

Citrus plants In vivo (mice)
Inhibited cell death and degeneration by down-regulation of IL-6 and TNF-α [66] Asiaticoside

Citrus plants In vivo (mice)
Inhibited cell death and degeneration by down-regulation of IL-6 and TNF-α [66] Asiaticoside

Citrus plants In vivo (mice)
Inhibited cell death and degeneration by down-regulation of IL-6 and TNF-α [66] Asiaticoside

Citrus plants In vivo (mice)
Inhibited cell death and degeneration by down-regulation of IL-6 and TNF-α [66] Asiaticoside

Citrus plants In vivo (mice)
Inhibited cell death and degeneration by down-regulation of IL-6 and TNF-α [66] Asiaticoside

Morinda lucida
In vivo (Sprague-Dawley rats) Reducing MDA level and NO activity [75] Morin

Plant-Derived Bioactive Compounds and Combinatorial Approaches for the Management of Neurodegenerative Disorders
In recent years, combination regimens have been explored in which researchers use plant-derived bioactive compounds in conjunction with other drugs to achieve higher efficacy and overcome the toxicities associated with the standard drugs of neurodegenerative diseases. Currently, drugs such as donepezil, amantadine, galantamine, apomorphine, rasagiline, riluzole, baclofen, entacapone, memantine, pramipexole, rivastigmine, carbidopa, dantrolene, and ropinirole are prescribed to treat different neurodegenerative disorders and associated problems. However, most of these drugs cause mild to severe side effects. In this section of the review, we included studies on donepezil, galantamine, and huperzine A combined with other phytocompounds.
Donepezil is prescribed by clinicians for treating dementias, but the medicine does not cure dementia. However, the drug may provide symptomatic treatment for AD, PD, and Lewy body dementia. A previous in vivo study showed that consumption of extravirgin olive oil rich in oleocanthal enhanced the effects of donepezil through significant reduction of amyloid β aggregation by regulating synaptic proteins and reducing neuroinflammation [103]. Donepezil and Ginkgo ketoester tablet combination exerts antiamnesic effects via antioxidation and concentration-dependent inhibition of acetylcholinesterase and butyrylcholinesterase, which have been closely linked to both the inactivation of brain-derived neurotrophic factor (BDNF) and tyrosine protein kinase B (TrkB) signaling pathways, as well as effects on oxidative stress and cholinergic pathway [104]. In a human study, 96 outpatients of AD were enrolled and each of them was administered Ginkgo biloba extract (EGb) (240 mg/day) and donepezil (5 mg/day for four weeks and then 10 mg/day) for 22 weeks, and the results suggested that combination therapy is superior to donepezil monotherapy and has lower side effects [105]. An in vitro study showed that caffeic acid (0.075 mg/mL) combined with donepezil (0.025 mg/mL) inhibited acetylcholinesterase and butyrylcholinesterase significantly, and donepezil (0.050 mg/mL) and caffeic acid (0.050 mg/mL) combination inhibited sodium nitroprusside-induced lipid peroxidation in rat brain homogenate the most [106]. Likewise, the activity of superoxide dismutase (SOD) and the content of malondialdehyde (MDA) were measured in resveratrol and donepeziltreated Wistar rats (colchicine-induced AD). The findings of the in vivo study revealed an improved antioxidant status, which was due to enhanced SOD activity in animal groups treated with donepezil and resveratrol combinations, implying that both drugs work synergistically [107]. In another in vivo study, Wistar rats were administered with donepezil alone and in combinations of donepezil and gallic acid, and the findings show that the combination of donepezil (10 mg/kg) and gallic acid (50 mg/kg) rectified rising MDA levels and brain activities of AChE and BChE, and the combination improved activities of SOD and catalase with a concomitant increase in thiol level, indicating synergistic effects of donepezil and gallic acid against AlCl 3 -induced neurotoxicity [108].
An interesting study used SIP3, a mixture of Santalum album, Illicium verum, and Polygala tenuifolia, and donepezil combinations, and the results showed improved memory and depression in a mouse model of AD as well as in vitro [109]. Pretreatment with quercetin significantly potentiated the efficacy of donepezil, evidenced through the improved cognitive memory in scopolamine-induced amnesia rats, which could have been due to the reduced levels of AChE and Aβ1-42 as well as elevated glutathione level, decreased lipid peroxidation, and reversal of neuronal damage in the treated groups [110]. Earlier, Stephaniae tetrandrae radix (STR), a commonly used traditional Chinese medicine, was widely used in the treatment of rheumatism, edema, and dysuria. Recently, STR was investigated to identify the pharmacologically important small compounds as well as their role in the neurodegenerative disorders, including AD. The study revealed that STR contains three alkaloids, cyclanoline, fangchinoline, and tetrandrine, as its major phytoconstituents. Among the three alkaloids, cyclanoline and fangchinoline suppressed AChE, but tetrandrine had no such enzymatic inhibition. However, pharmacological combinations of fangchinoline and huperzine A or donepezil inhibited AChE more than their individual treatments, implying synergistic effects [111]. Caffeine, an alkaloid, is the world's most consumed dietary component and is also regarded as a strong central-nervous-system stimulant. It is found mostly in coffee beans and Camellia sinensis leaves. In a recent study, caffeine's effects, either alone or in conjunction with donepezil, were investigated. Caffeine potentiated donepezil's actions in vitro by enhancing AChE inhibition and antioxidation. Co-administration of caffeine (50 or 100 mg/kg) and donepezil (5 mg/kg) inhibited AChE more effectively than in single dosages, although low caffeine consumption potentiated donepezil's antioxidant properties but had little effect on its inhibitory activity against AChE [112]. Harmine, an alkaloid derived from Peganum harmala, has been studied in vitro and in vivo for many pharmacological activities. Harmine has the capability to cross the blood-brain barrier and inhibit AChE activity [113]. Harmine (20 mg/kg) and donepezil (3 mg/kg) co-administration resulted in significant shortened escape latency and path length and improved memory in scopolamine-pretreated transgenic mice, which was linked to AChE inhibition in the cerebral cortex of mice. However, it was observed that the combination of harmine and donepezil did not inhibit Aβ protein aggregation in the hippocampus of scopolamine-treated and transgenic mice [114].
Genistein is a plant-derived isoflavone profoundly present in Glycine max, which has been investigated for its role in different diseases, including cancer and neurodegenerative diseases. In a recent study, genistein and galantamine combination was assessed in order to explore its neuroprotective effects against Aβ1-42-induced toxicity in AD, which was due to decreased genotoxicity and cell death [115]. In comparison to placebo and other cholinesterase inhibitors such as galantamine and donepezil, EGb7 (Gingko biloba extract) and memantine (cholinesterase inhibitor) were shown to be ineffective [116]. Huperzia serrata is an interesting medicinal plant used in traditional medication in Asia for treating cognitive impairment, dementia, and schizophrenia, and one of its compounds, huperzine A, is a well-established competitive reversible inhibitor of AChE. Huperzine A is a sesquiterpene alkaloid derived from Huperzia serrata that has been studied for its psychopharmacological effects, especially cognitive performance and neuroprotective effects that may be useful in the treatment of neurodegenerative disorders. Previously, it was reported that caffeic acid and ferrulic acid have the ability to potentiate huperzine A-mediated neuroprotective effects. Furthermore, they suggested that huperzine A in combination with either caffeic acid or ferrulic acid did not potentiate AChE inhibition in AD and memory deficits [117]. In a preclinical trial, memantine and huperzine A combination was identified as a superior AChE inhibitor than three other AChE inhibitors, including donepezil, rivastigmine, and galantamine. All four AChE inhibitors were effective in improving the mini-mental-state-examination (MMSE) and activities-of-daily-living (ADL) scores of AD patients when used in conjunction with memantine. However, huperzine A demonstrated superior effectiveness only when compared to other AChE inhibitors [118]. The antioxidant EGCG from Camellia sinensis (green tea) was investigated to see whether it could enhance the inhibitory effects of huperzine A on AChE activity in Alzheimer's disease. Notably, the study's findings revealed that EGCG is a poor inhibitor of AChE within a range of 10 to 300 mg/kg; however, EGCG addition substantially enhanced the inhibitory effects of huperzine A on AChE activity in AD, which might be attributed to EGCG's antioxidant action [119]. Other studies demonstrated that the combination of huperzine A with Convolvulus pluricaulis and Celastrus paniculatus improves cognitive function and health. The combinations of huperzine A with Convolvulus pluricaulis and Celastrus paniculatus showed better efficacy and synergistic AChE inhibition. However, no significant adverse toxic events were reported upon administering drug combinations [120].

Plants and Phytochemicals under Clinical Trials
Neurodegenerative disorders are debilitating and disabling, and their prevalence is increasing as the population ages. Therefore, the discovery of any therapeutics that stop or slow disease progression will help lessen the psychological and socio-economic burden. Notably, oxidative stress and inflammation are well-studied phenomena. Oxidative stress arises as a consequence of an imbalance between reactive oxygen species generation and the antioxidant system. A plethora of evidence clearly indicates that oxidative stress and mitochondrial dysfunction play a significant role in disease pathogenesis. Hence, various plant-derived compounds and their extracts targeting oxidative stress, neuroinflammation, and mitochondrial dysfunction have been documented to hold great promise in preclinical studies. In multitudinous preclinical studies, many plant extracts and their bioactive compounds have been demonstrated to be efficacious in treating neurodegenerative disorders, including AD, PD, TBI, and other diseases. These plant extracts and plant-derived bioactive compounds have great antioxidant, anti-apoptotic, and anti-inflammatory potential, which may help in neuroprotection. However, there is a significant gap in the clinical translation of these plant extracts and plant-derived bioactive compounds. For instance, according to a double-blinded phase II clinical trial (NCT01504854), resveratrol from red wine and the skin of red grapes may lower the risk of dementia by activating sirtuin proteins in aging and AD. Ethnodyne is a food supplement that is composed of plant-derived active components. In a clinical trial (NCT02815800), ethnodyne and vitamin B2 were tested against PD, and the results suggested that the combination improved motor and non-motor signs of the disease. Guar beans, rich in gum and fiber, have previously been shown to be effective in limiting inflammation and delaying the onset and progression of multiple sclerosis [121]. Chronic constipation commonly affects the gastrointestinal health of PD patients, and in a recent clinical trial (NCT04569656), guar gum rich in galactomannan from the seeds of Cyamopsis Tetra-Gonolobus prevented bloating, flatulence, and meteorism. Cannabidiol from Cannabis sativa has been investigated for numerous pharmacological properties, including neuroprotective and neuromodulatory effects, and serves as an alternative approach to treating different CNS disorders [122]. In a randomized, double-blinded, placebo-controlled phase II clinical trial (NCT02818777), the tolerability and efficacy of cannabidiol were studied on tremors in PD.
Sulforaphane from cruciferous plants has been presented as an epigenetic modulator, antioxidant, and anti-inflammatory agent, and its usefulness in dopaminergic neuronal survival is well established. In a randomized phase II clinical trial (NCT05084365), sulforaphane was supplied to 100 PD patients for 24 weeks and was assessed for its safety, tolerability, cognitive functions, and motor symptoms. Acetylcholine is the key regulatory molecule for the transmission of messages between nerve cells, and it is being degraded by acetylcholinesterase. ZT-1 is a plant-derived extract that is used in China for the treatment of memory disorders. It mainly acts by blocking the activity of acetylcholinesterase, and thus ZT-1 restores acetylcholine levels. In a randomized, double-blinded clinical trial (NCT00423228), ZT-1 along with donepezil was investigated for its safety and efficacy in AD. SCI-110 is a drug combination of dronabinol (a synthetic analogue of tetrahydrocannabinol from the Cannabis plant) and palmitoylethanolamide (PEA). In a phase II clinical trial (NCT05239390), combinations of dronabinol (2.5-12.5 mg) and 800 mg PEA were supplied to AD patients and studied for their tolerability, safety, appetite, and sleep quality. NIC5-15 is a naturally occurring small compound found in soy and other plants, and it was shown in a randomized, double-blind, phase II clinical trial (NCT01928420) to inhibit β-amyloid accumulation in AD. In a clinical trial (NCT04812418), combination extracts of the plants eschscholtzia (120 mg) and valerian (50 mg) were supplied in the form of tablets to study their efficacy against anxiety and sleep disorders. The effects of dietary strawberry supplementation on age-related problems were studied in a clinical trial (NCT02051140), and the results showed that it improved cognition and mobility by protecting against oxidative stress and inflammation. Similarly, in another clinical trial (NCT01888848), dietary blueberry supplementation improved cognition and mobility by protecting against oxidative stress and inflammation. In a clinical trial (NCT05609890), the safety and efficacy of many plant formulations (saffron, lemon balm, valerian, and tea extract) were assessed for sleep quality. This indicates the medicinal importance of plant extracts against neurodegenerative disorders, but there are very few studies on plant-derived compounds with regards to neurodegenerative disorders.

Conclusions, Challenges, and Future Directions
Current available drugs have been documented to exert several severe side effects, and disease complexity also worsens the patient's health even after treating the patient with standard symptomatic treatments, which limits the scope of the standard therapies against neurodegenerative disorders. Despite the promising results reported by several researchers, there is still a knowledge gap in terms of pharmacokinetics and pharmacodynamics of several plant-derived bioactive compounds in human clinical studies. In addition, critical clinical-translation challenges include dose optimization, product consistency, and quality control of the plant formulations and plant-derived bioactive compounds for different neurodegenerative disorders. Importantly, plant formulations and plant-derived compounds benefit and, simultaneously, suffer from low bioavailability and rapid renal clearance. Moreover, plasma concentrations of such plant-derived bioactive compounds present in the diet are significantly lower than the pharmacological doses needed in vitro and in vivo to trigger neuroprotective responses. Therefore, it is reasonable to predict the pharmacological and chemopreventive doses, which may help fill the knowledge gaps in the disease severity and complexity. In past few decades, numerous preclinical studies showed that plant formulations and plant-derived compounds possess enormous chemopreventive and therapeutic potential against many neurodegenerative disorders. Therefore, there has been increasing interest in identifying chemopreventive and therapeutic formulations and bioactive compounds obtained from plants that could lead to the development of novel therapeutic options to curb the increasing burden of neurodegenerative disorders throughout the world. Notably, managing neurodegenerative disorders through selective plant formulations and plant-derived bioactive compounds that are capable of crossing the blood-brain barrier represents a novel, safe, affordable, and alternative option to standard therapies for the prevention and treatment of neurodegenerative disorders. Therefore, this review integrates recent in vitro and in vivo experimental data that suggest the potential plant formulations and plant-derived bioactive compounds targeting molecular culprits involved in abnormal protein dynamics, neuroinflammation, and oxidative stress in neurodegenerative diseases. Due to their anti-cholinesterase, antioxidant, anti-inflammatory, anti-aggregation, and anti-apoptotic effects, plant formulations as well as plant-derived bioactive compounds may provide huge chemopreventive and therapeutic benefits in the drug development against neuroinflammation, oxidative stress, protein aggregation, and apoptosis induction in neuronal cells. Herein, we also review in vitro and in vivo bioactivities and critically appraise the most plausible active plant-derived bioactive compounds.In addition, we summarize cellular and molecular targets and mechanisms of action of plant-derived bioactive compounds. Investigations on plant formulations and plant-derived bioactive compounds revealed that plant-based diets are a rich source of flavonoids, terpenes, phenolics, carotenoids, sterols, and anthocyanins as well as vitamins and minerals. Hence, consuming a plant-based diet that contains such phytochemicals may lead to potential health benefits, including neuroprotection, hepatoprotection, cardioprotection, and others.