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Review
. 2020 Aug 12;8(8):284.
doi: 10.3390/biomedicines8080284.

Neuroprotection: Targeting Multiple Pathways by Naturally Occurring Phytochemicals

Andleeb Khan  1 , Sadaf Jahan  2 , Zuha Imtiyaz  3 , Saeed Alshahrani  1 , Hafiz Antar Makeen  4 , Bader Mohammed Alshehri  2 , Ajay Kumar  5 , Azher Arafah  6 , Muneeb U Rehman  6
Affiliations
Review

Neuroprotection: Targeting Multiple Pathways by Naturally Occurring Phytochemicals

Andleeb Khan et al. Biomedicines. .

Abstract

With the increase in the expectancy of the life span of humans, neurodegenerative diseases (NDs) have imposed a considerable burden on the family, society, and nation. In defiance of the breakthroughs in the knowledge of the pathogenesis and underlying mechanisms of various NDs, very little success has been achieved in developing effective therapies. This review draws a bead on the availability of the nutraceuticals to date for various NDs (Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, vascular cognitive impairment, Prion disease, Spinocerebellar ataxia, Spinal muscular atrophy, Frontotemporal dementia, and Pick's disease) focusing on their various mechanisms of action in various in vivo and in vitro models of NDs. This review is distinctive in its compilation to critically review preclinical and clinical studies of the maximum phytochemicals in amelioration and prevention of almost all kinds of neurodegenerative diseases and address their possible mechanism of action. PubMed, Embase, and Cochrane Library searches were used for preclinical studies, while ClinicalTrials.gov and PubMed were searched for clinical updates. The results from preclinical studies demonstrate the efficacious effects of the phytochemicals in various NDs while clinical reports showing mixed results with promise for phytochemical use as an adjunct to the conventional treatment in various NDs. These studies together suggest that phytochemicals can significantly act upon different mechanisms of disease such as oxidative stress, inflammation, apoptotic pathways, and gene regulation. However, further clinical studies are needed that should include the appropriate biomarkers of NDs and the effect of phytochemicals on them as well as targeting the appropriate population.

Keywords: natural products; neurodegenerative diseases; neuroprotection; phytochemicals.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Chemical structures of some common phytochemicals used in the prevention of neurodegenerative diseases (NDs).
Figure 2
Figure 2
Flow diagram showing the search strategy, the number of records identified, and the included/excluded studies [16].
Figure 3
Figure 3
Schematic representation of the several mechanisms associated with Alzheimer’s Disease (AD) and their possible prevention by some phytochemicals. The main hallmarks of AD; amyloid plague and NFT are prevented by curcumin and luteolin via GSK 3β pathway. Curcumin, genistin, and luteolin decreases the oxidative stress in the neuron. Neuroinflammation is also inhibited by genistin and apigenin. The pathway of apoptosis, activated in AD is blocked by the use of apigenin. Apigenin also activates BDNF/ERK/CREB pathway leading to neuronal survival.
Figure 4
Figure 4
Diagrammatic presentation of Parkinson’s disease, cause, and role of phytochemicals to reverse the sign of PD. Mitochondrial dysfunction, oxidative stress, and uncontrolled cell death leads to the accumulation of Lewy bodies and resultant neuronal damage. Phytochemicals function with multiple targets. Curcumin targets the inducible nitric oxide synthase (iNOS) and regulates the ratio of BCL-2/BAX which leads to the restoration of mitochondrial function. Genistin increases the activity of SOD, Catalase, and GSH and protect the neurons from damage ignited by oxidative stress. Resveratrol inhibits the formation of Lewy body (aggregation of α-syn protein-a major cause of PD). Rutin protects the neuron by leading the anti-inflammatory pathway and EGCG inhibits the transcriptional factor NFκB and restores the normal function of mitochondria. EGCG also plays a role to inhibit DNA fragmentation. All over the activities of phytochemicals escape neurons from damage.
Figure 5
Figure 5
Diagrammatic presentation of Huntington Disease progression and protection of neurons with phytochemicals: 6-35 CAG repeats lead to the formation of Huntingtin protein which consequently accumulates in the neurons and damage motor neurons. In the early stage, damaged motor neurons result in short term memory while on a later stage, this condition changes into depression, weight loss, and many more. The studied phytochemicals generally work against free radicals and restrict the accumulation of Huntingtin protein in the cells. This inhibition further leads to neuronal survival. Resveratrol works on LC3 lipidation while protopanaxtriol and viniferin leads to the antioxidative pathway and restore the function of mitochondria to protect the neurons and stop further accumulation of Huntingtin protein in neurons.
Figure 6
Figure 6
Overall pathogenesis of neuronal loss in ischemic stroke and their prevention by phytochemicals. Oxidative stress, found in the neurons of the ischemic brain is prevented by resveratrol and curcumin. These phytochemicals also prevent the inflammation and apoptosis induced by oxidative stress. Baicalein prevents the formation of inflammasome reducing inflammation and edema. Resveratrol activates SMO/GLI pathway leading to the development of hippocampal neuronal circuit. It also activates the PI3K/Akt/mTOR pathway leading to cell survival. Another phytochemical ginkgolide B acts on MEK/ERK/SOCS2 pathway causing inhibition of inflammation in neurons.
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