Neuroprotective Effects of Berberine and Caffeine in Parkinson's Disease

Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor impairments and the progressive loss of dopaminergic neurons in the substantia nigra. The pathological features of PD include the aggregation of alpha-synuclein (α-syn), neuroinflammation, and oxidative stress. Traditional pharmacological treatments focus on alleviating symptoms but do not halt disease progression. Recent studies highlight the potential of natural compounds, particularly berberine (BBR) and caffeine (CAF), in providing neuroprotection against PD-related impairments. This article explores the mechanisms by which BBR and CAF may exert neuroprotective effects, focusing on their roles in mitigating neuroinflammation, oxidative stress, and α-syn aggregation.

Mechanisms of Arachidonic Acid in Cancer Progression

The arachidonic acid (AA) pathway plays a critical role in cancer biology by modulating immune responses and influencing tumor progression. Arachidonic acid is a polyunsaturated fatty acid that serves as a precursor for bioactive lipids, including prostaglandins, leukotrienes, and hydroxyeicosatetraenoic acids (HETE), which can either promote or suppress antitumor immunity (Tredicine et al., 2025).

Eicosanoid Production

Eicosanoids, derived from AA, are produced via three primary enzymatic pathways: cyclooxygenases (COX), lipoxygenases (LOX), and cytochrome P450 (CYP450). The COX pathway is particularly well-studied for its role in inflammation and cancer. COX-2, an inducible enzyme, is often overexpressed in tumors and contributes to tumor growth by producing PGE2, which promotes angiogenesis and immune evasion (Tredicine et al., 2025).

Dual Role of Eicosanoids

The dual nature of eicosanoids complicates their role in cancer. While some promote tumor growth, others, such as lipoxins (derived from LOX activity), can exert anti-inflammatory effects and help resolve inflammation, creating a balance that could be therapeutically targeted for cancer treatment (Tredicine et al., 2025).

Role of m6A RNA Modification in Liver Disease

N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic RNAs and plays a crucial role in regulating gene expression through various mechanisms, including mRNA stability, splicing, and translation (Matsuda et al., 2025). In the context of metabolic dysfunction-associated steatotic liver disease (MASLD), m6A modification has been linked to the regulation of autophagy and the response to oxidative stress, suggesting its potential as a therapeutic target (Matsuda et al., 2025).

m6A Modification and Autophagy

Recent findings suggest that m6A modification can influence autophagic processes, which are vital for maintaining cellular homeostasis, especially in the liver where lipid metabolism is crucial (Matsuda et al., 2025). Dysregulation of autophagy is associated with the development of MASLD, and targeting m6A pathways may offer new therapeutic strategies to enhance liver function and mitigate disease progression.

Impact of Hypertension on Depression and Brain Function

Hypertension often coexists with depression, creating a complex interplay that exacerbates both conditions. The relationship between hypertension and depression is mediated by several factors, including inflammation, oxidative stress, and alterations in neurotransmitter levels (Zhao et al., 2025).

Neuroinflammation and Depression

In hypertensive states, inflammatory cytokines can penetrate the blood-brain barrier, leading to neuroinflammation and subsequent neuronal damage, particularly in areas of the brain associated with mood regulation (Zhao et al., 2025). This inflammation can disrupt the balance of neurotransmitters such as serotonin and norepinephrine, contributing to depressive symptoms.

Tri-Culture Model for Studying Neuroinflammation

To better understand the interactions between vascular endothelial cells, neurons, and microglia in the context of hypertension-related depression, a tri-culture model has been developed. This model allows for the evaluation of cellular responses to hypertensive conditions and the potential therapeutic effects of compounds like BBR and CAF (Zhao et al., 2025).

Therapeutic Strategies in Combating Neurodegenerative Disorders

The combination of BBR and CAF presents a novel therapeutic strategy for neuroprotection in PD. Both compounds have been shown to possess anti-inflammatory and antioxidant properties, making them suitable candidates for intervention in neurodegenerative processes.

Berberine

BBR is a natural alkaloid with a range of pharmacological effects, including anti-inflammatory and antioxidant actions. It has been shown to inhibit the aggregation of α-syn and promote dopamine release, highlighting its potential as a neuroprotective agent in PD (Waheeb et al., 2025).

Caffeine

CAF, another natural compound, enhances dopamine levels and inhibits monoamine oxidase activity, further contributing to its neuroprotective effects. Recent studies have suggested that the combination of BBR and CAF may work synergistically to reduce neuroinflammation and oxidative stress, thereby improving motor functions in PD models (Waheeb et al., 2025).

Conclusion

The neuroprotective effects of BBR and CAF in Parkinson’s disease highlight the potential of natural compounds in managing neurodegenerative disorders. Through their combined actions on inflammation, oxidative stress, and neurotransmitter modulation, these compounds may offer new avenues for therapeutic intervention. Further research is essential to fully elucidate the mechanisms underlying their protective effects and to optimize their use in clinical settings.

References

1. Tredicine, M., Mucci, M., & Mattoscio, D. (2025). Immunoregulatory mechanisms of the arachidonic acid pathway in cancer. FEBS Lett
2. Matsuda, S., Nakashima, M., Fukumoto, A., Suga, N., & Antunes, L. M. G. (2025). N6-Methyladenosine Modification in the Metabolic Dysfunction-Associated Steatotic Liver Disease. Nutrients. https://doi.org/10.3390/nu17071158
3. Zhao, H., Huang, L., Liu, J., Feng, M., & Ren, W. Q. (2025). A vascular endothelial cell, neuron, and microglia tri-culture model to study hypertension-related depression. Front Cell Neurosci. https://doi.org/10.3389/fncel.2025.1553309
4. Waheeb, T. S., Abdulkader, M. A., Ghareeb, D. A., & Moustafa, M. E. (2025). Neuroprotective efficacy of berberine and caffeine against rotenone‐induced neuroinflammatory and oxidative disturbances associated with Parkinson’s disease via inhibiting α-synuclein aggregation and boosting dopamine release. Neurotox Res. https://doi.org/10.1007/s10787-025-01661-w