What is Mental Health?
Mental health relates to your emotional, psychological, and social well-being. It affects how you think, feel, and act – a Mind/Body Connection. It also helps determine how you handle stress, relate to others, and make choices. Mental health is important at every stage of life, from childhood and adolescence through adulthood. In 2017, an estimated 11.2 million (4.5%) adults in the U.S., had a severe psychological condition, according to the National Institute of Mental Health (NIMH). Mental illnesses, such as depression, are the third most common cause of hospitalization in the U.S., and adults living with serious mental illness die on average 25 years earlier than others [Kessler et al 2007].
Everyone has some risk of developing a mental health disorder, irrespective of their age, sex, income, or ethnicity. Several factors can affect mental health such as your genes or brain chemistry; life experiences (i.e. trauma or abuse); family history of mental disorders; as well as your lifestyle including diet, physical activity, and substance use. Poor mental condition can also affect your physical state and increase the risk for stroke, type 2 diabetes, and heart disease. Therefore, a basic knowledge on brain chemistry and its related functions may help design proper lifestyle measures to improve your mental health and optimize your overall well-being.
Brain – the ‘Commander-in-Chief’ of Your Body
The brain is an organ with a large mass of nerve tissue located in the skull. It is made up of two types of tissue, the grey matter, and the white matter. Grey matter is involved in analyzing information, whereas the white matter transmits information between the grey matter areas. The ratio of grey to white matter changes over the lifespan. In general, the brain can be divided into three major functional regions:
- Frontal region (Cerebrum), the largest part of the brain with two halves or hemispheres – right and left. The right hemisphere controls the left side of the body, and the left hemisphere controls the right side. Their functions include motor skills, temperature, touch, vision, hearing, reasoning, problem solving, emotions, and learning.
- Mid region (Brain Stem) includes the pons, and the medulla that connects to the spinal cord. It contains nerve fibers that carry signals to all parts of the body. The brain stem also regulates bodily functions such as consciousness, fatigue, heart rate, and blood pressure. Damage to the brain stem can cause loss of consciousness.
- Basal region (Cerebellum) is located at the base of the skull with a curved mass of nerve tissue. It regulates voluntary muscle movements and to maintain posture, balance, and homeostasis.
Your body is controlled by your brain with billions of neurons that communicate through chemical signals collectively known as neurotransmission or synapse.
Neurotransmission – Your ‘Brain-Body Connection’
Neurotransmitters play an important role in neural communication. They are chemical messengers that carry messages between nerve cells (neurons) and other cells in your body. This uninterrupted signaling process sustains brain activity and influences every function from breathing to heartbeat to mood to involuntary movements. This process is generally referred to as neuro- or synaptic transmission. A neurotransmitter influences a neuron in one of three ways: excitatory, inhibitory or modulatory. An excitatory transmitter promotes the generation of an electrical signal called an action potential in the receiving neuron, while an inhibitory transmitter prevents it. Whether a neurotransmitter is excitatory or inhibitory depends on the receptor it binds to. Neuromodulators are not restricted between two neurons, and so can affect large numbers of neurons at once. The brain uses specific neurotransmitters to instruct specific physiological functions at designated target sites in your body (TABLE).
TABLE: Neurotransmitters and their specific brain-associated functions
Most neurotransmitters are either small molecules, amino acids, or neuropeptides. There are about a dozen known neurotransmitters and more than 100 different neuropeptides. Maintaining optimum levels of neurotransmitters requires a healthy balanced diet to provide the brain with vital neuro-chemical building blocks to support their synthesis, transportation, and activity. Although various diets may contain neurotransmitters and their precursors, their ability to reach the brain depends on how easily they can cross the Blood-Brain Barrier (BBB). Neurotransmitters like dopamine and serotonin cannot cross the BBB due to lack of necessary ‘transport’ mechanisms.
Diets and supplements may contain neurotransmitters and precursors; however, their benefits on mental health depends on how these chemicals cross the BBB and reach the brain. Specific transport mechanisms or ‘Trojan Horse-like’ carriers that can ferry such vital nutrients across the BBB are quintessential for cognitive health outcomes.
Blood Brain Barrier (BBB) – the ‘Gatekeeper’ of Your Body’s ‘Central Intelligence Hub’
The BBB is a unique dynamic regulatory interface located at the border between the blood stream and the brain. The BBB protects the brain against circulating toxins or harmful microbial pathogens. As the ‘gatekeeper’ to the central nervous system (CNS), the BBB facilitates uptake of vital nutrients, vitamins, and hormones to sustain cerebral growth and metabolism, as well as in maintaining the cerebral ionic and volume balance [Sharif et al 2018].
Therefore, the delivery of nutrients to the central nervous system (CNS) pose several challenges, among which the BBB is the critical limitation [Moradi et al 2020]. To cross the BBB, various approaches have been evaluated including the carrier-mediated delivery systems and use of specific ligands for transport/target delivery. Most proteins in the plasma can not cross the BBB due to their size and hydrophilicity. Only few specific proteins such as lactoferrin (LF), insulin, insulin-like growth factors and vasopressin cross the BBB by a receptor-mediated transcytosis [Laterra et al 1999].
LACTOFERRIN: Innate transport molecule that facilitates delivery of nutrients across the BBB
Lactoferrin is an innate iron-binding transport protein that facilitates nutrient delivery into the brain by crossing the BBB [Ji et al 2006]. Differentiated brain capillary endothelial cells demonstrate specific lactoferrin-binding receptors. Lactoferrin binds to these receptors on the cell surface and transports the covalently bound molecules across the cell membrane via receptor-mediated, transporter-mediated or adsorption-mediated transcytosis [Huang et al 2007]. Lactoferrin is rapidly mobilized into the brain and accumulates in the cytoplasm of vascular endothelial cells in the neocortex, striatum, hippocampus, and thalamus [Kopaeva et al 2019].
Lactoferrin has been widely used as a functional component in the medical, food, veterinary, and cosmetic industries. Lactoferrin-based materials, such as complexes, nanoparticles, hydrogels, and emulsions, to encapsulate, protect and deliver bioactive compounds is gaining increasing attention [Liu et al 2018]. Lactoferrin-conjugated polyethylene-glycol (PEG) liposomes or solid lipid nanoparticles (SLN) are shown to facilitate the diffusion of molecules across the BBB and are effective target delivery systems for loading diagnostics or therapeutics for various brain conditions [Huang et al 2013, Singh et al 2016]. A novel lactoferrin-based PORTIN® technology is currently used in the dietary supplement industry for target delivery of bioactive nutrients to specific tissue sites in the body, i.e. synovial joint [Naidu 2011].
The innate ability of lactoferrin to cross the BBB and transport vital bioactive molecules has led to the development of target delivery systems for drugs and nutrients. A novel lactoferrin-based PORTIN® technology is currently used in the dietary supplement industry for target delivery of bioactive nutrients to specific tissue sites in the body.
LACTOFERRIN: A natural neuroprotective agent to support regular cognitive functions
Lactoferrin is synthesized in the dopaminergic (DA) neurons and activated microglial cells of the brain [Fillebeen et al 2001]. Lactoferrin is considered as a conditional nutrient for neurodevelopment, neuroprotection, and cognitive function during the neonatal brain growth [Wang et al 2016]. The multifunctional role of lactoferrin in infant food formula includes: i) modulation of about 10 genes involved in the brain-derived neurotrophin factor signaling pathway in the hippocampus, crucial for neurodevelopment and cognition; ii) upregulation of markers for neuroplasticity and growth of axons; and iii) enhance cognitive function and learning [Chen et al 2015].
Intrauterine Growth Restriction (IUGR) refers to an impaired development of the fetus, which results in adverse neurodevelopmental and psychiatric consequences later in life. Maternal supplementation of lactoferrin could provide beneficial nutritional intervention and revert certain IUGR-induced sequelae, including brain hippocampal changes in neonates [Somm et al 2014]. Lactoferrin supplemented milk formulations demonstrate neuroprotective benefits on brain metabolism, as well as on cerebral gray and white matter recovery. Nutritional intervention with lactoferrin may be of high interest for the clinical management of preterm brain neuroprotection. Lactoferrin is shown to combat oxidative stress induced impairment of neurons; and partially reverse the microstructure alterations [van de Looij et al 2019]. Several human randomized clinical trials (RCTs) from past three decades have established lactoferrin as a major evidence-based nutraceutical for infant food formulations and clinical nutrition [Lönnerdal 2014].
Iron is involved brain metabolism in many important processes such as oxygen transportation, oxidative phosphorylation, and neurotransmitter synthesis. Abnormal iron homoeostasis leads to oxidative stress-associated cell damage, a major risk factor in neurodegeneration. During aging, iron accumulation in the brain could cause motor and cognitive impairment. A potential neuroprotective role for lactoferrin conjugated deferasirox in neurodegenerative disorder management through metal chelation therapy has been reported [Kamalinia et al 2013].
Lactoferrin is present in several types of neurons and considered as a conditional nutrient for neurodevelopment, neuroprotection, and cognitive function during the neonatal brain growth. Several human studies have established lactoferrin a major evidence-based nutraceutical for infant food formulations and clinical nutrition.
LACTOFERRIN: Multifunctional nutritional that helps in stress management and restful sleep
Oral administration of lactoferrin seems to benefit in reversing stress-induced changes in the humoral and cellular immune responses [Zimecki & Artym 2004]. Lactoferrin has a role in inhibiting free radical formation and protecting against DNA damage. Lactoferrin could inhibit distress perception via opioid mediated mechanism(s) and help avert any possible immune suppression from psychosocial stress [Sacharczuk et al 2005]. Lactoferrin could also induce relaxation of the endothelium-intact but not of the endothelium-denuded aortic rings. Thus, lactoferrin may support healthy blood pressure via an endothelium-dependent vasodilation mediated by nitric oxide (NO·) production [Hayashida et al 2004].
Lactoferrin acts as an adaptogen and helps reduce stress-induced surges of corticosterone levels within 30 min [Aleshina et al 2016]. In vivo, the mood-boosting effect of lactoferrin was demonstrated in a repeated forced-swim test (FST) stress in animal models. Oral administration of lactoferrin is shown to play a role in down-regulating dopamine and serotonin release in the brains and support healthy locomotor function [Izumo et al 2020]. A clinically tested lactoferrin-based nutritional technology to improve human sleep patterns has been developed [Naidu et al 2013]. Severe, repeated or chronic stress leads to negative health outcomes including disruptions of the sleep/wake cycle. Lactoferrin is shown to reduce the negative physiological impacts of stress and facilitate non-rapid eye movement (NREM) sleep consolidation as well as enhanced rapid eye movement (REM) sleep rebound [Thompson et al 2017].
Oral administration of lactoferrin can help against stress-induced negative health outcomes and facilitate a healthy sleep/wake cycle. Lactoferrin plays a role as an adaptogen with mood-boosting benefits. It effectively down-regulates the dopamine and serotonin release in brains and supports recovery of healthy locomotor function.
Take Home Message
Mental well-being is a major public health concern worldwide. The current pandemic with quarantine measures, social distancing and life-style restrictions are implicated in psychological distress and compromised physical performance of individuals of both genders and all age groups. Generalized recommendations such as a balanced diet, regular exercise, yoga and meditation should be practiced; however, overall mental health is contingent upon the bioavailability of functional neurochemical blocks to the brain and its CNS. It should be noted that the BBB is the body’s designated ‘gatekeeper’ that strictly regulates the movement of vital nutrients in-and-out of the brain and its CNS. Therefore, a mere presence of a nutrient or a vitamin in a dietary plan or a supplement regimen will not ensure its crossing the BBB and bioavailability to its target site – the brain, unless there is a specific delivery mechanism. Only a few molecules in your body possess such unique ability to cross the BBB. Lactoferrin, an iron-binding glycoprotein in your body fluids, is one such extraordinary transport module! Recently in pharmacology and nutritional science, lactoferrin has emerged as a promising target-delivery system for effective delivery of bioactive compounds across the BBB. Combined with its multifunctional spectrum, lactoferrin is a promising all-natural nutraceutical that can help promote regular brain function and optimum mental health.
- Aleshina GM, Yankelevich IA, Zhakharova ET, Kokryakov VN. Ross Fiziol Zh Im I M Sechenova. 2016;102(7):846-851.
- Chen Y, Zheng Z, Zhu X, et al. Lactoferrin promotes early neurodevelopment and cognition in postnatal piglets by upregulating the BDNF signaling pathway and polysialylation. Mol Neurobiol. 2015;52(1):256-269.
- Fillebeen C, Ruchoux MM, Mitchell V, et al. Lactoferrin is synthesized by activated microglia in the human substantia nigra and its synthesis by the human microglial CHME cell line is upregulated by tumor necrosis factor alpha or 1-methyl-4-phenylpyridinium treatment. Brain Res Mol Brain Res. 2001;96(1-2):103-113.
- Hayashida K, Takeuchi T, Ozaki T, et al. Bovine lactoferrin has a nitric oxide-dependent hypotensive effect in rats. Am J Physiol Regul Integr Comp Physiol. 2004;286(2):R359-R365.
- Huang FY, Chen WJ, Lee WY, Lo ST, Lee TW, Lo JM. In vitro and in vivo evaluation of lactoferrin-conjugated liposomes as a novel carrier to improve the brain delivery. Int J Mol Sci. 2013;14(2):2862-2874.
- Huang RQ, Ke WL, Qu YH, Zhu JH, Pei YY, Jiang C. Characterization of lactoferrin receptor in brain endothelial capillary cells and mouse brain. J Biomed Sci. 2007;14(1):121-128.
- Izumo N, Yukiko I, Kagaya N, et al. Lactoferrin suppresses decreased locomotor activities by improving dopamine and serotonin release in the amygdala of ovariectomized rats. Curr Mol Pharmacol. 2020;10.2174/1570163817666200430002937.
- Ji B, Maeda J, Higuchi M, et al. Pharmacokinetics and brain uptake of lactoferrin in rats. Life Sci. 2006;78(8):851-855.
- Kamalinia G, Khodagholi F, Atyabi F, et al. Enhanced brain delivery of deferasirox-lactoferrin conjugates for iron chelation therapy in neurodegenerative disorders: in vitro and in vivo studies. Mol Pharm. 2013;10(12):4418-4431.
- Kessler RC, Angermeyer M, Anthony JC, et al. Lifetime prevalence and age-of-onset distributions of mental disorders in the World Health Organization's World Mental Health Survey Initiative. World Psychiatry. 2007;6(3):168-176.
- Kopaeva Y, Cherepov AB, Zarayskaya IY, Nesterenko MV. Transport of Human Lactoferrin into Mouse Brain: Administration Routes and Distribution. Bull Exp Biol Med. 2019;167(4):561-567.
- Laterra J, Keep R, Betz LA, et al. Blood-Brain Barrier. In: Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th Siegel GJ, Agranoff BW, Albers RW, et al. (Eds.). 1999. Philadelphia: Lippincott-Raven.
- Liu f, Zhang S, Li J, et al. Recent development of lactoferrin-based vehicles for the delivery of bioactive compounds: Complexes, emulsions, and nanoparticles. Trends in Food Sci Technol. 2018;79:67-77.
- Lönnerdal B. Infant formula and infant nutrition: bioactive proteins of human milk and implications for composition of infant formulas. Am J Clin Nutr. 2014;99(3):712S-7S.
- Moradi SZ, Momtaz S, Bayrami Z, Farzaei MH, Abdollahi M. Nano-formulations of herbal extracts in treatment of neurodegenerative disorders. Front Bioeng Biotechnol. 2020;8:238.
- Naidu AS, Naidu AGT, Naidu SAG. Coenzyme Q10, Lactoferrin and Angiogenin compositions and uses thereof. US Patent No.8021659 B2, Issued Sep 20, 2011.
- Naidu AS, Naidu AGT, Naidu SAG. Metallo-lactoferrin-coenzyme compositions to improve sleep patterns. US Patent No.8476223, Issued July 2, 2013.
- Sacharczuk M, Zagulski T, Sadowski B, et al. Lactoferrin in the central nervous system. Neurol Neurochir Pol. 2005;39(6):482-489.
- Sharif Y, Jumah F, Coplan L, et al. Blood brain barrier: A review of its anatomy and physiology in health and disease. Clin Anat. 2018;31(6):812-823.
- Singh I, Swami R, Pooja D, et al. Lactoferrin bio-conjugated solid lipid nanoparticles: a new drug delivery system for potential brain targeting. J Drug Target. 2016;24(3):212-223.
- Somm E, Larvaron P, van de Looij Y, et al. Protective effects of maternal nutritional supplementation with lactoferrin on growth and brain metabolism. Pediatr Res. 2014;75(1-1):51-61.
- Thompson RS, Roller R, Mika A, et al. Dietary Prebiotics and Bioactive Milk Fractions Improve NREM Sleep, Enhance REM Sleep Rebound and Attenuate the Stress-Induced Decrease in Diurnal Temperature and Gut Microbial Alpha Diversity. Front Behav Neurosci. 2017;10:240. Published 2017 Jan 10. doi:10.3389/fnbeh.2016.00240
- van de Looij Y, Larpin C, Cabungcal JH, et al. Nutritional intervention for developmental brain damage: Effects of lactoferrin supplementation in hypocaloric induced intrauterine growth restriction rat pups. Front Endocrinol (Lausanne). 2019;10:46.
- Wang B. Molecular Determinants of Milk Lactoferrin as a Bioactive Compound in Early Neurodevelopment and Cognition. J Pediatr. 2016;173 Suppl:S29-S36.
- Zimecki M, Artym J. The effect of psychic stress on the immune response]. Postepy Hig Med Dosw (Online). 2004;58:166-175.
ABOUT THE AUTHOR
Dr. Sreus Naidu, PharmD, MS (Regulatory Science), brings over ten years of leadership experience in health industry. He specializes in the research, development and commercialization of novel health technologies. Sreus is an inventor, with multiple patents in various health applications. He has extensive clinical experience, having provided patient care at numerous hospitals, medical centers, as well as, international clinics. He is a member of several professional organizations and holds multiple government licensures.