Advantages and limitations of phytochemical therapeutics in neuroprotection.
| Aspect | Advantages | Limitations |
|---|---|---|
| Multi-target activity | Simultaneously modulate multiple pathological pathways, including MAPK9/JNK, oxidative stress, neuroinflammation, mitochondrial dysfunction, and apoptosis. | Multi-target effects may complicate mechanistic interpretation and target validation. |
| Safety profile | Generally exhibit lower toxicity and better tolerability compared to many synthetic drugs. | Long-term safety data are often lacking, particularly at therapeutic doses. |
| Natural origin | Derived from medicinal plants with extensive historical use in traditional medicine systems. | Variability in plant source, cultivation conditions, and harvesting practices can affect quality and efficacy. |
| Antioxidant activity | Efficiently scavenge reactive oxygen species (ROS) and enhance endogenous antioxidant defences. | Antioxidant effects observed in vitro may not always translate into clinical efficacy. |
| Anti-inflammatory effects | Suppress pro-inflammatory cytokines and signalling pathways such as MAPK9 and NF-κB. | Limited understanding of optimal dosing regimens required to achieve sustained anti-inflammatory effects in humans. |
| Neuroprotective potential | Protects neurons from apoptosis, mitochondrial dysfunction, excitotoxicity, and protein aggregation. | Most evidence is derived from preclinical studies rather than large-scale clinical trials. |
| Blood-brain barrier (BBB) penetration | Certain compounds, such as berberine, resveratrol, and epigallocatechin gallate (EGCG), demonstrate partial BBB permeability. | Many phytochemicals exhibit poor BBB penetration, limiting therapeutic concentrations within the brain. |
| Bioavailability | Some compounds can be optimised through formulation technologies and structural modifications. | Poor solubility, rapid metabolism, and low oral bioavailability remain major challenges for compounds such as curcumin and quercetin. |
| Drug development potential | Serve as valuable lead compounds for the design of novel neuroprotective drugs targeting MAPK9. | Isolation, purification, and large-scale production may be costly and technically challenging. |
| Combination therapy | Can be combined with conventional drugs to enhance efficacy and reduce adverse effects through synergistic mechanisms. | Potential herb-drug interactions may influence pharmacokinetics and treatment outcomes. |
| Precision medicine applications | It may be tailored to individual molecular profiles and disease mechanisms in future personalised therapies. | Biomarkers for patient stratification and treatment monitoring remain inadequately validated. |
| Computational drug discovery | Integration with molecular docking, AI, machine learning, and network pharmacology accelerates candidate identification. | Computational predictions require extensive experimental and clinical validation before translation. |
| Standardisation and quality control | Advances in phytochemical characterisation improve consistency and reproducibility. | Lack of universal standards for extraction, formulation, and quality assessment remains a significant challenge. |
| Clinical translation | Growing interest from academia and industry supports further development. | Significant translational gaps exist between promising laboratory findings and successful clinical outcomes. |
The authors would like to acknowledge the University of the Witwatersrand’s Research Office for awarding Dr. Otun a postdoctoral fellowship.
SO: Investigation, Writing—original draft. IA: Conceptualization, Supervision, Writing—review & editing. Both authors read and approved the submitted version.
The authors declare no conflicts of interest.
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Open access funding provided by the University of the Witwatersrand, and the authors would like to acknowledge the National Research Foundation (NRF) of South Africa for awarding Prof. Achilonu the CPRR research grant (Grant number CPRR23042899244). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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