A Review Article: Pharmacology of Phytochemicals in Neurodegenerative Disorders

Abstract

Neurodegenerative disorders (NDs), including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, are growing conditions characterized by neuronal loss, cognitive decline, and motor impairment. Current pharmacological treatments generally offer symptomatic relaxation and are insufficient to halt disease progress. Phytochemicals—bioactive compounds derived from plants such as polyphenols, flavonoids, alkaloids, terpenoids , and stilbenes—have emerged as promising candidates due to their multi-target therapeutic potential. The compounds exhibit antioxidant, anti-inflammatory, anti-amyloidogenic, and mitochondrial-protective activities, while further regulating neurotransmission and proteostasis. Prominent phytochemicals such as curcumin, resveratrol, EGCG, quercetin, ginsenosides , and huperzine A have explained neuroprotective effects in preclinical and early clinical studies Still, challenges such as poor solubility, poor bioavailability, fast metabolism, and lack of standardized formulations limit their clinical translation. Emerging planning , containing Nano carriers, liposomal systems, and solid lipid nanoparticles, offer enhanced delivery and brain targeting. Additionally, personalized medicine approaches, biomarker-based clinical trials, and combination therapies with conventional drugs may improve treatment outcomes. This review specifies an overview of the pharmacological mechanisms of key phytochemicals in NDs, evaluates current evidence, and highlights future prospects and challenges in their therapeutic growth. Advancing the compounds from bench to bedside requires rigorous clinical confirmation, optimized formulations, and regulatory standardization

Introduction

Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are marked by progressive, irreversible neuronal loss, leading to memory, cognitive, and motor impairments. They represent a major public health challenge, especially as global populations age. Currently available treatments are mainly symptomatic and do not halt disease progression.

II. Pathophysiology and Causes

These disorders are multifactorial in origin and involve:

• Protein misfolding and aggregation (e.g., amyloid-β, tau, α-synuclein)

• Mitochondrial dysfunction and energy failure

• Oxidative and nitrosative stress

• Chronic neuroinflammation

• Excitotoxicity (excessive glutamate activity)

• Impaired proteostasis (protein clearance)

• Ageing, genetic mutations, environmental toxins, and lifestyle factors play key roles in disease onset and progression.

III. Types of Neurodegenerative Disorders

Key disorders include:

1. Alzheimer’s Disease (AD) – memory loss, amyloid plaques, tau tangles

2. Parkinson’s Disease (PD) – motor decline due to dopamine neuron loss

3. Huntington’s Disease (HD) – inherited, causes motor and psychiatric symptoms

4. ALS and MND – motor neuron degeneration, muscle weakness

5. Multiple System Atrophy (MSA) – autonomic and motor dysfunction

6. Frontotemporal Dementia (FTD) – personality and language changes

7. Prion Diseases – rapidly progressive, fatal brain disorders

IV. Diagnosis

Diagnosis is based on:

• Clinical assessments (e.g., MMSE, MoCA)

• Imaging (MRI, CT, PET scans for protein buildup)

• Biomarkers in cerebrospinal fluid or blood (e.g., tau, amyloid-β)

• Genetic testing for familial disorders

• Emerging digital biomarkers (robotic/motion tracking)

V. Current Treatments

A. Pharmacological:

• Symptomatic drugs: Cholinesterase inhibitors, Levodopa, NMDA antagonists

• Disease-modifying agents: e.g., Miglustat for NPC, antibodies in clinical trials

• Psychiatric symptom management: SSRIs, antipsychotics

B. Non-Pharmacological:

• Physical therapy and exercise

• Cognitive and behavioral therapies

• Nutritional and lifestyle interventions (e.g., Mediterranean diet)

• Assistive technologies (robotics, digital tools)

• Multidisciplinary care for improved outcomes

VI. Role of Phytochemicals in Neurodegeneration

Phytochemicals are bioactive compounds from plants with neuroprotective potential. They offer multi-targeted therapeutic effects, which is crucial due to the complex pathology of neurodegenerative diseases.

Key Benefits:

• Antioxidant and anti-inflammatory properties

• Anti-amyloid and anti-apoptotic effects

• Improved mitochondrial function

• Regulation of neurotransmitters

• Activation of protective pathways (e.g., Nrf2, sirtuins)

Major Classes of Phytochemicals:

1. Polyphenols – Curcumin, resveratrol, EGCG (green tea)

2. Flavonoids – Quercetin, kaempferol; enhance cognition, reduce inflammation

3. Alkaloids – Galantamine, Huperzine A; inhibit acetylcholinesterase

4. Terpenoids – Ginkgolides; improve memory, cerebral blood flow

5. Saponins – Ginsenosides; reduce amyloid/tau aggregation

6. Carotenoids – Lutein, β-carotene; antioxidant defense

7. Stilbenes – Resveratrol; activates cellular survival pathways

Mechanisms of Action:

• Free radical scavenging

• Reduction of inflammatory cytokines

• Prevention of toxic protein buildup

• Support for mitochondrial energy systems

• Metal ion chelation to prevent oxidative damage

VII. Challenges and Future Directions

Despite promising preclinical evidence, challenges remain in clinical translation:

• Low bioavailability, poor solubility, rapid metabolism

• Variability in plant sources and formulations

Recent research focuses on:

• Enhanced delivery systems

• Standardizing dosages

• Understanding molecular mechanisms

• Integrating phytochemicals into therapeutic frameworks

Conclusion

Phytochemicals represent a promising multi-target strategy against neurodegenerative disorders by addressing the core pathological processes—oxidative stress, neuroinflammation, mitochondrial dysfunction, protein aggregation and synaptic failure. Preclinical evidence summarized in this review demonstrates that diverse classes (polyphenols, flavonoids, alkaloids, terpenoids) exert antioxidant, anti-amyloidogenic, anti-inflammatory and mitochondria-stabilizing effects and can modulate neurotransmission and proteostasis. However, clinical translation remains limited by poor bioavailability, variable formulations, short and underpowered trials, and inconsistent quality control of botanical materials. To move phytochemicals from nutraceutical promise to therapeutic reality, the field needs standardized botanical characterization, optimized delivery platforms (e.g., nanocarriers), biomarker-driven and adequately powered clinical trials, and rational combination or precision-medicine approaches. With these coordinated steps, phytochemicals could become effective adjuncts in multimodal management of neurodegenerative disease. And large-scale clinical trials to confirm therapeutic efficacy. With proper formulation and validation, phytochemicals could offer safe, effective, and affordable strategies for delaying the progression of neurodegenerative diseases and improving the quality of life of affected individuals

References

[1] T. Farooqui and A. A. Farooqui, Neuroprotective effects of phytochemicals in neurological disorders. John Wiley & Sons, 2017. [2] D. K. Yadav, ‘Potential therapeutic strategies of phytochemicals in neurodegenerative disorders’, Current Topics in Medicinal Chemistry, vol. 21, no. 31, pp. 2814–2838, Dec. 2021, doi: 10.2174/1568026621666211201150217 [3] B. K. Velmurugan, B. Rathinasamy, B. P. Lohanathan, V. Thiyagarajan, and C.-F. Weng, ‘Neuroprotective role of phytochemicals’, Molecules, vol. 23, no. 10, p. 2485, Sep. 2018, doi: 10.3390/molecules23102485. [4] R. Venkatesan, E. Ji, and S. Y. Kim, ‘Phytochemicals that regulate neurodegenerative disease by targeting neurotrophins: a comprehensive review’, BioMed Research International, vol. 2015, pp. 1–22, 2015, doi: 10.1155/2015/814068. [5] R. N. L. Lamptey, B. Chaulagain, R. Trivedi, A. Gothwal, B. Layek, and J. Singh, ‘A review of the common neurodegenerative disorders: current therapeutic approaches and the potential role of nanotherapeutics’, IJMS, vol. 23, no. 3, p. 1851, Feb. 2022, doi: 10.3390/ijms23031851. [6] J. Chand and G. Subramanian, ‘Neurodegenerative disorders: types, classification, and basic concepts’, in Multi-Factorial Approach as a Therapeutic Strategy for the Management of Alzheimer’s Disease, G. M. Ashraf, A. T. Zari, Md. H. Rahman, C. Karthika, and V. V. S. R. Karri, Eds., Singapore: Springer Nature, 2024, pp. 31–40. Doi: 10.1007/978-981-96-0259-9_2 [7] C. Majee, R. Mazumder, and B. Pantela, ‘Neurodegenerative disorders: concepts, types, and treatment strategies’, in Nanomedicine for Neurodegenerative Disorders, Apple Academic Press, 2025. [8] M. Saake et al., ‘Erratum to “Clinical/perfusion CT CBV mismatch as prognostic factor in intraarterial thrombectomy in acute anterior circulation stroke” [Clin. Neurol. Neurosurg. 121 (2014) 39–45]’, Clinical Neurology and Neurosurgery, vol. 125, p. 239, Oct. 2014, doi: 10.1016/j.clineuro.2014.06.018. [9] D. A. Dean et al., ‘A systematic assessment of the association of polysomnographic indices with blood pressure: the multi-ethnic study of atherosclerosis(Mesa)’, Sleep, vol. 38, no. 4, pp. 587–596, Apr. 2015, doi: 10.5665/sleep.4576. [10] ‘Motor neurone disease’, nhs.uk. Accessed: Sep. 30, 2025. [Online]. Available: https://www.nhs.uk/conditions/motor-neurone-disease/ [11] J. M. Statland, R. J. Barohn, A. L. McVey, J. Katz, and M. M. Dimachkie, ‘Patterns of weakness, classification of motor neuron disease & clinical diagnosis of sporadic als’, Neurol Clin, vol. 33, no. 4, pp. 735–748, Nov. 2015, doi: 10.1016/j.ncl.2015.07.006. [12] G. Tesco and S. Lomoio, ‘Pathophysiology of neurodegenerative diseases: an interplay among axonal transport failure, oxidative stress, and inflammation?’, Semin Immunol, vol. 59, p. 101628, Jan. 2022, doi: 10.1016/j.smim.2022.101628. [13] M. Relja, ‘Pathophysiology and classification of neurodegenerative diseases’, EJIFCC, vol. 15, no. 3, pp. 97–99, Aug. 2004, Accessed: Oct. 05, 2025. [Online]. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034184/ [14] J. Graff-Radford, D. T. Jones, and N. R. Graff-Radford, ‘Pathophysiology of language, speech and emotions in neurodegenerative disease’, Parkinsonism & Related Disorders, vol. 20, pp. S49–S53, Jan. 2014, doi: 10.1016/S1353-8020(13)70014-2 [15] M. F. Beal, ‘Energetics in the pathogenesis of neurodegenerative diseases’, Trends in Neurosciences, vol. 23, no. 7, pp. 298–304, Jul. 2000, doi: 10.1016/S0166-2236(00)01584-8. [16] A. Xiarchos, ‘Robotic systems involved in the diagnosis of neurodegenerative diseases’, Adv Exp Med Biol, vol. 1194, p. 423, 2020, doi: 10.1007/978-3-030-32622-7_39 [17] J.-C. García and R.-H. Bustos, ‘The genetic diagnosis of neurodegenerative diseases and therapeutic perspectives’, Brain Sciences, vol. 8, no. 12, p. 222, Dec. 2018, doi: 10.3390/brainsci8120222. [18] M. Gómez-Río, M. Moreno Caballero, J. Manuel Górriz Sáez, and A. Mínguez-Castellanos, ‘Diagnosis of neurodegenerative diseases: the clinical approach’, CAR, vol. 13, no. 5, pp. 469–474, Mar. 2016, doi: 10.2174/1567205013666151116141603. [19] S. Danev and D. St. Stoyanov, ‘Early noninvasive diagnosis of neurodegenerative diseases’, Folia Medica, vol. 52, no. 2, Jan. 2010, doi: 10.2478/v10153-010-0041-y [20] G. N. Hajj, Ed., Young perspectives for old diseases: recent updates on the understanding and therapies for neurodegenerative diseases. Erscheinungsort nicht ermittelbar: Bentham Science Publishers, 2015. [21] I. Cariati, L. Masuelli, R. Bei, V. Tancredi, C. Frank, and G. D’Arcangelo, ‘Neurodegeneration in niemann–pick type c disease: an updated review on pharmacological and non-pharmacological approaches to counteract brain and cognitive impairment’, IJMS, vol. 22, no. 12, p. 6600, Jun. 2021, doi: 10.3390/ijms22126600. [22] A. Bogdan, V. Manera, A. Koenig, and R. David, ‘Pharmacologic approaches for the management of apathy in neurodegenerative disorders’, Front. Pharmacol., vol. 10, Jan. 2020, doi: 10.3389/fphar.2019.01581 [23] E. Angelopoulou et al., ‘Pharmacological and non-pharmacological treatments for depression in parkinson’s disease: an updated review’, Medicina, vol. 59, no. 8, p. 1454, Aug. 2023, doi: 10.3390/medicina59081454. [24] M. Pache, H. Kedar, S. Kond, P. Jadhav, and T. Kedar, ‘Pharmacological management of neurodegenerative disorders current and future approaches’, International Journal of Scientific Research and Technology, Mar. 2025, doi: 10.5281/zenodo.15074000. [25] L. Nahar et al., ‘Natural products in neurodegenerative diseases: recent advances and future outlook’, Front. Pharmacol., vol. 16, Mar. 2025, doi: 10.3389/fphar.2025.1529194. [26] H. L. Hernández?Montiel et al., ‘Phytochemicals effects on neurodegenerative diseases’, in Fruit and Vegetable Phytochemicals, 1st ed., E. M. Yahia, Ed., Wiley, 2017, pp. 85–114. Doi: 10.1002/9781119158042.ch4. [27] A. Singh, R. Kukreti, L. Saso, and S. Kukreti, ‘Oxidative stress: a key modulator in neurodegenerative diseases’, Molecules, vol. 24, no. 8, p. 1583, Apr. 2019, doi: 10.3390/molecules24081583. [28] E. P. De Lima et al., ‘Polyphenols, alkaloids, and terpenoids against neurodegeneration: evaluating the neuroprotective effects of phytocompounds through a comprehensive review of the current evidence’, Metabolites, vol. 15, no. 2, p. 124, Feb. 2025, doi: 10.3390/metabo15020124. [29] G. P. Kumar and F. Khanum, ‘Neuroprotective potential of phytochemicals’, Pharmacogn Rev, vol. 6, no. 12, pp. 81–90, 2012, doi: 10.4103/0973-7847.99898. [30] G. D’Onofrio et al., ‘Phytochemicals in the treatment of alzheimer’s disease: a systematic review’, Current Drug Targets, vol. 18, no. 13, pp. 1487–1498, Oct. 2017, doi: 10.2174/1389450117666161102121553. [31] B. Koul, U. Farooq, D. Yadav, and M. Song, ‘Phytochemicals: a promising alternative for the prevention of alzheimer’s disease’, Life, vol. 13, no. 4, p. 999, Apr. 2023, doi: 10.3390/life13040999. [32] S. Shoaib et al., ‘Plant-derived bioactive compounds in the management of neurodegenerative disorders: challenges, future directions and molecular mechanisms involved in neuroprotection’, Pharmaceutics, vol. 15, no. 3, p. 749, Feb. 2023, doi: 10.3390/pharmaceutics15030749. [33] P. K. Garlapati, A. K. Raghavan, and N. Shivanna, ‘Phytochemicals having neuroprotective properties from dietary sources and medicinal herbs’, Phcog J, vol. 7, no. 1, pp. 1–17, Dec. 2014, doi: 10.5530/pj.2015.7.1. [34] V. Thakur et al., ‘Phytochemicals for the treatment of cns disorders’, in Natural Scaffolds for Prevention and Treatment of Neurodegenerative Disorders, 1st ed., Boca Raton: CRC Press, 2025, pp. 235–268. Doi: 10.1201/9781003403241-15. [35] J. Wang, Y. Song, M. Gao, X. Bai, and Z. Chen, ‘Neuroprotective effect of several phytochemicals and its potential application in the prevention of neurodegenerative diseases’, Geriatrics, vol. 1, no. 4, p. 29, Nov. 2016, doi: 10.3390/geriatrics1040029. [36] A. Dey and J. N. De, ‘Neuroprotective therapeutics from botanicals and phytochemicals against Huntington’s disease and related neurodegenerative disorders’, Journal of Herbal Medicine, vol. 5, no. 1, pp. 1–19, Mar. 2015, doi: 10.1016/j.hermed.2015.01.002. [37] B. O. Dareowolabi, E.-Y. Moon, and J. H. Kim, ‘The therapeutic potential of dietary phytochemicals in age-related neurodegenerative disorders’, Pharmaceuticals, vol. 18, no. 9, p. 1268, Aug. 2025, doi: 10.3390/ph18091268. [38] Md. H. Rahman et al., ‘Therapeutic potential of natural products in treating neurodegenerative disorders and their future prospects and challenges’, Molecules, vol. 26, no. 17, p. 5327, Sep. 2021, doi: 10.3390/molecules26175327. [39] H. Sharma and P. Chandra, ‘Challenges and future prospects: a benefaction of phytoconstituents on molecular targets pertaining to alzheimer’s disease’, Int J. Pharm. Investigation, vol. 14, no. 1, pp. 117–126, Dec. 2023, doi: 10.5530/ijpi.14.1.15. [40] Md. R. Islam et al., ‘A clinical study and future prospects for bioactive compounds and semi-synthetic molecules in the therapies for Huntington’s disease’, Mol Neurobiol, vol. 61, no. 3, pp. 1237–1270, Mar. 2024, doi: 10.1007/s12035-023-03604-4. [41] S. Raja, C. Sengupta, K. Rajagopalan, L. Inbathamizh, S. Sudha, and J. D. S. Christyraj, ‘Future trends and directives for research on phytochemicals in neurological diseases’, in NeuroPhytomedicine, CRC Press, 2024. [42] T. Berman and A. Bayati, ‘What are Neurodegenerative Diseases and How Do They Affect the Brain?’, Front. Young Minds, vol. 6, p. 70, Dec. 2018, doi: 10.3389/frym.2018.00070. [43] J. A. Evans, P. Mendonca, and K. F. A. Soliman, ‘Neuroprotective Effects and Therapeutic Potential of the Citrus Flavonoid Hesperetin in Neurodegenerative Diseases’, Nutrients, vol. 14, no. 11, p. 2228, May 2022, doi: 10.3390/nu14112228 [44] V. Castelli et al., ‘Neuronal Cells Rearrangement During Aging and Neurodegenerative Disease: Metabolism, Oxidative Stress and Organelles Dynamic’, Front. Mol. Neurosci., vol. 12, p. 132, May 2019, doi: 10.3389/fnmol.2019.00132 [45] B. Pekdemir et al., ‘Mechanisms and Potential Benefits of Neuroprotective Agents in Neurological Health’, Nutrients, vol. 16, no. 24, p. 4368, Dec. 2024, doi: 10.3390/nu16244368.

Copyright

Copyright © 2025 Arif Aasidulla Pathan, Asma Firdous, Arsalan Javed Shariff, Rubina Sheikh, Prerona Das. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.