Induction of Salivary Neuromodulators by Chanting and Breathing Exercise

A. SPECIFIC AIMS

SA1: Obtain a preliminary estimate of the extent to which a structured chanting exercise stimulates salivary secretion that contains quantifiable amounts of NGF in healthy subjects.

SA2: Obtain a preliminary estimate of the extent to which a structured breathing exercise stimulates salivary secretion that contains quantifiable amounts of NGF in healthy subjects.

B. BACKGROUND AND SIGNIFICANCE BACKGROUND Neurodegenerative Diseases Neurodegenerative diseases such as Alzheimer's disease are a major healthcare concern globally. In the USA, AD is the 6th leading cause of death. Both genetic and non-genetic factors contribute to the development of AD. Individuals affected with AD require supports ranging from medications, assisting devices and personal care that pose an enormous emotional and financial burden. AD is associated with significant alterations at the molecular level that eventually translates into cellular, tissue, organ and systemic dysfunction. Therefore, molecular therapy that alters cell functions has been a major clinical option for treating AD . For example, NGF, a trophic factor involved in the development, maintenance and survival of peripheral nervous system and the cholinergic neurons of the central nervous system, show significant reduction in AD subjects. The reduction in NGF causes significant decline in cognitive functions. Therefore administration of NGF is followed as a viable clinical option for AD subjects. In addition to these therapeutic options, non-pharmacological modes of treatment such as meditation and yoga have been considered as alternative approaches to treat AD. Such practices and life-styles are deeply rooted in several ancient cultures. This project is based on two life-style health practices from the ancient Tamil culture.

NGF Nerve growth factor (NGF) is a neurotrophic protein (MW=13 kDa). NGF is produced by every tissue/organ that is innervated by sensory afferents and/or sympathetic efferents, as well as by central (CNS) and peripheral (PNS) nervous system, and immune cells. NGF is important for the functional integrity of cholinergic neurons in CNS and for the development and functional integrity of neurons in PNS. NGF is a survival, differentiation and trophic factor for cells of the immune system and epithelial origin. Salivary glands (submandibular/submaxillary) produce a large amount of NGF in humans and in mice. NGF produced from mouse submaxillary glands is used in several clinical trials. In CNS, NGF is produced in the cortex, the hippocampus and in the pituitary gland; and also in other areas, including the basal ganglia, thalamus, spinal cord and in the retina. NGF binds to its receptor TrkA and activates the mitogenic MAPK, PI3K/Akt and PLC-gamma pathways to mediate cell growth, differentiation and survival. NGF mediated survival is important for the basal forebrain complex (BFC) cholinergic neurons. These neurons contribute to consciousness, memory, attention and arousal. BFC neurons are highly affected in neurodegenerative diseases such as AD. NGF protects BFC neurons in experimental trauma models, and in age-associated cholinergic decline. Due to the positive effects of NGF in multiple systems, development of NGF as a drug is actively pursued for treating neurodegeneration, immune dysregulation, chronic inflammation and autoimmune diseases. However, until recently clinical trials with NGF have been without much success because of hyperalgesia. Recent studies are showing that gene therapy, nasal and ocular routes of NGF administration to be effective with much less nociceptive side effect. Moreover, a recent finding that chemical modification of NGF reduces pain is considered as a new direction in NGF therapy. A Phase II clinical trial assessing the beneficial effects of an adeno-associated virus mediated expression of NGF in the cholinergic neurons of the brain is underway at MUSC involving the co-investigator of this project Dr. Jacobo Mintzer.