Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifically, a neurotoxin or neurotoxicant– alters the normal activity of the nervous system in such a way as to cause permanent or reversible damage to nervous tissue. This can eventually disrupt or even kill neurons, which are cells that transmit and process signals in the brain and other parts of the nervous system. Neurotoxicity can result from organ transplants, radiation treatment, certain drug therapies, recreational drug use, exposure to heavy metals, bites from certain species of venomous snakes, pesticides, certain industrial cleaning solvents, fuels and certain naturally occurring substances. Symptoms may appear immediately after exposure or be delayed. They may include limb weakness or numbness, loss of memory, vision, and/or intellect, uncontrollable obsessive and/or compulsive behaviors, delusions, headache, cognitive and behavioral problems and sexual dysfunction. Chronic mold exposure in homes can lead to neurotoxicity which may not appear for months to years of exposure. All symptoms listed above are consistent with mold mycotoxin accumulation.
Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factor (NGF), a family which also includes NT-3 and NT-4/NT-5. Neurotrophic factors are found in the brain and the periphery. BDNF was first isolated from a pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.
Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, glycogen synthase (GS), GSK-3 has since been identified as a protein kinase for over 100 different proteins in a variety of different pathways. In mammals, including humans, GSK-3 exists in two isozymes encoded by two homologous genes GSK-3α (GSK3A) and GSK-3β (GSK3B). GSK-3 has been the subject of much research since it has been implicated in a number of diseases, including type 2 diabetes, Alzheimer's disease, inflammation, cancer, addiction and bipolar disorder.
Tropomyosin receptor kinase A (TrkA), also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor type 1, or TRK1-transforming tyrosine kinase protein is a protein that in humans is encoded by the NTRK1 gene.
Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the NTRK2 gene. TrkB is a receptor for brain-derived neurotrophic factor (BDNF). The standard pronunciation for this protein is "track bee".
Tropomyosin receptor kinase C (TrkC), also known as NT-3 growth factor receptor, neurotrophic tyrosine kinase receptor type 3, or TrkC tyrosine kinase is a protein that in humans is encoded by the NTRK3 gene.
Monoclonal antibodies (mAbs) have varied therapeutic uses. It is possible to create a mAb that binds specifically to almost any extracellular target, such as cell surface proteins and cytokines. They can be used to render their target ineffective, to induce a specific cell signal, to cause the immune system to attack specific cells, or to bring a drug to a specific cell type.
Trk receptors are a family of tyrosine kinases that regulates synaptic strength and plasticity in the mammalian nervous system. Trk receptors affect neuronal survival and differentiation through several signaling cascades. However, the activation of these receptors also has significant effects on functional properties of neurons.
Neurotrophic factor receptors or neurotrophin receptors are a group of growth factor receptors which specifically bind to neurotrophins.
Taxifolin (5,7,3',4'-flavan-on-ol), also known as dihydroquercetin, belongs to the subclass flavanonols in the flavonoids, which in turn is a class of polyphenols. It is extracted from plants such as Siberian larch and milk thistle.
Norwogonin, also known as 5,7,8-trihydroxyflavone (5,7,8-THF), is a flavone, a naturally occurring flavonoid-like chemical compound which is found in Scutellaria baicalensis. It has been found to act as an agonist of the TrkB, the main signaling receptor of brain-derived neurotrophic factor (BDNF), and appears to possess roughly the same activity in this regard to that of the closely related but more well-known tropoflavin (7,8-DHF).
Tropoflavin, also known as 7,8-dihydroxyflavone, is a naturally occurring flavone found in Godmania aesculifolia, Tridax procumbens, and primula tree leaves. It has been found to act as a potent and selective small-molecule agonist of the tropomyosin receptor kinase B (TrkB), the main signaling receptor of the neurotrophin brain-derived neurotrophic factor (BDNF). Tropoflavin is both orally bioavailable and able to penetrate the blood–brain barrier. A prodrug of tropoflavin with greatly improved potency and pharmacokinetics, R13, is under development for the treatment of Alzheimer's disease.
Deoxygedunin, or 14,15-deoxygedunin, is a tetranortriterpenoid isolated from the Indian neem tree a plant that has been in traditional Indian medicine since ancient times as a remedy for various ailments.
ANA-12 is a selective, small-molecule non-competitive antagonist of TrkB, the main receptor of brain-derived neurotrophic factor (BDNF). The compound crosses the blood-brain-barrier and exerts central TrkB blockade, producing effects as early as 30 minutes and as long as 6 hours following intraperitoneal injection in mice. It blocks the neurotrophic actions of BDNF without compromising neuron survival.
LM22A-4 is a synthetic, selective small-molecule partial agonist of TrkB (EC50 for TrkB activation = 200–500 pM; IC50 for inhibition of BDNF binding to TrkB = 47 nM; IA = ~85%), the main receptor of brain-derived neurotrophic factor. It has been found to possess poor blood-brain-barrier penetration when administered systemically, so LM22A-4 has been given to animals instead via intranasal administration, with central nervous system TrkB activation observed. The compound produces neurogenic and neuroprotective effects in animals, and shows beneficial effects on respiration in animal models of Rett syndrome.
R7 is a small-molecule flavonoid and orally active, potent, and selective agonist of the tropomyosin receptor kinase B (TrkB) – the main signaling receptor for the neurotrophin brain-derived neurotrophic factor (BDNF) – which is under development for the treatment of Alzheimer's disease. It is a structural modification and prodrug of tropoflavin (7,8-DHF) with improved potency and pharmacokinetics, namely oral bioavailability and duration.
Entrectinib, sold under the brand name Rozlytrek, is an anti-cancer medication used to treat ROS1-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. It is a selective tyrosine kinase inhibitor (TKI), of the tropomyosin receptor kinases (TRK) A, B and C, C-ros oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK).
R13 is a small-molecule flavonoid and orally active, potent, and selective agonist of the tropomyosin receptor kinase B (TrkB) – the main signaling receptor for the neurotrophin brain-derived neurotrophic factor (BDNF) – which is under development for the potential treatment of Alzheimer's disease. It is a structural modification and prodrug of tropoflavin (7,8-DHF) with improved potency and pharmacokinetics, namely oral bioavailability and duration. The compound is a replacement for the earlier tropoflavin prodrug R7 and has similar properties to it. It was developed because while R7 displayed a good drug profile in animal studies, it showed almost no conversion into tropoflavin in human liver microsomes. In contrast to R7, R13 is readily hydrolyzed into tropoflavin in human liver microsomes.
Neurotrophin mimetics are small molecules or peptide like molecules that can modulate the action of the neurotrophin receptor. One of the main causes of neurodegeneration involves changes in the expression of neurotrophins (NTs) and/or their receptors. Indeed, these imbalances or changes in their activity, lead to neuronal damage resulting in neurological and neurodegenerative conditions. The therapeutic properties of neurotrophins attracted the focus of many researchers during the years, but the poor pharmacokinetic properties, such as reduced bioavailability and low metabolic stability, the hyperalgesia, the inability to penetrate the blood–brain barrier and the short half-lives render the large neurotrophin proteins not suitable to be implemented as drugs.
