Lactoferrin for Mental Health: Neuro-Redox Regulation and Neuroprotective Effects across the Blood-Brain Barrier with Special Reference to Neuro-COVID-19

Abstract

Overall mental health depends in part on the blood-brain barrier, which regulates nutrient transfer in-and-out of the brain and its central nervous system. Lactoferrin, an innate metal-transport protein, synthesized in the substantia nigra, particularly in dopaminergic neurons and activated microglia is vital for brain physiology. Lactoferrin rapidly crosses the blood-brain barrier via receptor-mediated transcytosis and accumulates in the brain capillary endothelial cells. Lactoferrin receptors are additionally present on glioma cells, brain micro-vessels, and neurons. As a regulator of neuro-redox, microglial lactoferrin is critical for protection/repair of neurons and healthy brain function. Iron imbalance and oxidative stress are common among patients with neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, dementia, depression, and multiple sclerosis. As an endogenous iron-chelator, lactoferrin prevents iron accumulation and dopamine depletion in Parkinson’s disease patients. Oral lactoferrin supplementation could modulate the p-Akt/PTEN pathway, reduce Aβ deposition, and ameliorate cognitive decline in Alzheimer’s disease. Novel lactoferrin-based nano-therapeutics have emerged as effective drug-delivery systems for clinical management of neurodegenerative disorders. Recent emergence of the Coronavirus disease-2019 (COVID-19) pandemic, initially considered a respiratory illness, demonstrated a broader virulence spectrum with the ability to cross the blood-brain barrier and inflict a plethora of neuropathological manifestations in the brain – the Neuro-COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are widely reported in Parkinson’s disease, Alzheimer’s disease, dementia, and multiple sclerosis patients with aggravated clinical outcomes. Lactoferrin, credited with several neuroprotective benefits in the brain could serve as a potential adjuvant in the clinical management of Neuro-COVID-19.

KEYWORDS:

• Alzheimer’s disease
• brain tumor
• blood-brain barrier
• COVID-19
• Lactoferrin
• mental health
• neurological symptoms
• Neuro-COVID-19
• Parkinson’s Disease
• Redox
• SARS-CoV-2

Disclosure statement

The authors SAGN and ASN are affiliated with N-terminus Research Laboratory. The authors TCW and KJAD have no potential conflict of interest to disclose.

Dedication

Clyde F. Wallace, Jr, born June 9^th, 1949 in Hopkinsville Kentucky passed on December 2^nd, 2020 due to a COVID-19 infection that occurring amongst his fight with Parkinson’s disease. He was a natural born teacher and mentor who dedicated his life’s work to local community education, particularly among those underserved children in Christian County, Kentucky. In 1987 the Governor of Kentucky conferred upon him the status of Colonel, the highest title of honor bestowed by the Commonwealth of Kentucky, for his contributions and outstanding service to advancing education in the state. Wallace is survived by his son, Dr. Taylor C. Wallace.

Additional information

Notes on contributors

Sreus A. G. Naidu

Dr. Sreus A. G. Naidu, MS, PharmD, has earned Doctorate in Pharmacy and MS in Regulatory Science from the University of Southern California. Sreus has over 15 years of experience working at N-terminus Research Laboratory based in California, which specializes in the isolation, purification, and activation of bioactive molecules. He is co-inventor on multiple patents with applications in human nutrition and animal healthcare.

Taylor C. Wallace

Professor Taylor C. Wallace, PhD, CFS, FACN, is Principal and CEO at the Think Healthy Group and an Adjunct Professor in the Department of Nutrition and Food Studies at George Mason University. Dr. Wallace’s background includes a PhD in Food Science and Nutrition from The Ohio State University. He is a fellow of the American College of Nutrition and is the 2015 recipient of the Charles A. Regus Award, given by the American College of Nutrition for original research and innovation in the field of nutrition. Dr. Wallace is a Senior Fellow of the Center for Magnesium Education & Research, the Editor-in-chief of the Journal of the Dietary Supplements, Deputy Editor-in-chief of the Journal of the American College of Nutrition, the editor of six academic textbooks, author of over 50 peer-reviewed manuscripts and book chapters, and author of the popular cookbook, Sizzling Science.

Kelvin J. A. Davies

Professor Kelvin J. A. Davies, PhD, DSc, MAE, FRSC, FRCP, FLS, FRI, is the James E. Birren Chair and Dean of Faculty at the University of Southern California’s, Leonard Davis School of Gerontology. He is also Distinguished Professor of Molecular and Computational Biology and Biochemistry & Molecular Medicine. Davies was educated at London and Liverpool Universities, the University of Wisconsin, Harvard University, and the University of California at Berkeley. Previously, he was a faculty member at Harvard University, Harvard Medical School, and Albany Medical College. He pioneered the study of protein oxidation and proteolysis during adaptation to oxidative stress and discovered stress-genes including calcineurin regulator RCAN1 whose mis-regulation contributes to Alzheimer and Huntington diseases and Down syndrome. He demonstrated that impaired induction of Proteasome and Lon protease genes contributes to senescence and diminished stress-resistance and has pioneered the concept of impaired ‘Adaptive Homeostasis’ as a major factor in aging. Davies has been awarded 15 honorary Doctoral degrees and has been elected as a fellow of 14 national and international academies including AAAS, Royal Society of Medicine, Royal Society of Chemistry, Royal College of Physicians, and Academy of Europe. He was knighted in 2012 as a chevalier of France’s Ordre National du Mérite and elevated as a Knight Commander in 2018.

A. Satyanarayan Naidu

Professor A Satyanarayan Naidu, PhD, FACN, FLS, FISSVD, is the Director of N-terminus Research Laboratory in California, USA. After receiving PhD in Medical Microbiology (1985) from the Osmania University in India, Dr. Naidu served the Directorate of Public Health Services (DPHS), the Government of A.P., India and the World Health Organization (WHO) Surveillance program. He performed post-doctoral research at the Medical University of Pécs, Hungary and the Biomedical Center-Uppsala, Sweden. Dr. Naidu joined the faculty at the Lund University; Sweden (1988-1992), the University of North Carolina at Chapel Hill, USA (1993-1997). He was appointed as the Director at the Center for Antimicrobial Research, California State University-Pomona, USA (1998-2000). Dr. Naidu’s discoveries on Staphylococcal toxic shock syndrome (TSS) and E. coli hemolytic uremic syndrome (HUS) have garnered international recognition. He was principal investigator for several NIH grants, published more than 100 peer-reviewed research publications, written over 30 book chapters, and authored 4 reference volumes in the field of medical sciences. He holds 24 core patents, and his technology transfers in biomedical technology reach worldwide. Dr. Naidu is an elected fellow of the Royal Society for Medicine, the Linnean Society of London, the American College of Nutrition, and the International Society for the Study of Vulvovaginal Disease.