Neurotransmitters Functional Balance in Health and Disease Management

By:- Dr. C. S. Paulose
Molecular Neurobiology and Cell Biology Unit, Centre for Neuroscience, Head, Department of Biotechnology, Cochin University of Science and Technology, Cochin 682 022, Kerala, India. e-mail: cspaulose@cusat.ac.in

Abstract

The recent developments in neurobiology have rendered new prominence and potential to study about the structure and function of brain and related disorders. Human behaviour is the net result of neural control of the communication between brain cells. Neurotransmitters are chemicals that are used to relay, amplify and modulate electrical signals between neurons and/or another cell. It mediates rapid intercellular communication through the nervous system by interacting with cell surface receptors. These receptor subtypes often trigger second messenger signaling pathways that regulate the activity of ion channels. The functional balance of different neurotransmitters such as Acetylcholine (Ach), Dopamine (DA), Serotonin (5-HT), Norepinephrine (NE), Epinephrine (EPI), Glutamate and Gamma amino butyric acid (GABA) regulates the growth, division and other vital functions of a normal cell / organism. Any change in neurotransmitters’ functional balance will result in the failure of cell function and lead to the occurrence of diseases. Abnormalities in the production or functioning of neurotransmitters have been implicated in a number of neurological disorders like Schizophrenia, Alzheimer’s, Epilepsy, Depression and Parkinson’s disease. Changes in central and peripheral neuronal signaling system is also noted in diabetes, hypoglycaemia, hypoxia, cancer, cell proliferation, alcoholism and aging. Elucidation of neurotransmitters receptor interaction pathways and gene expression regulation by second messengers and transcriptional factors in health and disease conditions can lead to new small molecules for development of therapeutic agents to improve neurological disease conditions. Increased awareness of the global effects of neurological disorders should help health care planners and the neurological community set appropriate priorities in research, prevention and management of these diseases.

Key Words: Neurotransmitters, neurotransmission, neurological disorders, disease management.

Introduction

Neurons are the basic cell of the brain and nervous system. Neurons communicate to each other by releasing neurotransmitters. Neurotransmitters are the chemicals which account for the transmission of signals from one neuron to the next across synapses. It transmits information within the brain and from the brain to all the parts of the body. Neurotransmitters exert their effect by binding to specific receptors on the neuronal postsynaptic membrane. The activity of a neuron depends on the balance between the number of excitatory and inhibitory processes affecting it, either processes occurring individually or simultaneously. The consequences of the neurotransmitter receptor function can influence the regulation of metabolic manifestations in hypothyroidism, hypertension, diabetes and cell proliferation directly by central nervous system function or through the hypothalamic-pituitary-end organ axis. Hormones such as insulin, glucagon, thyroxine, tri- iodothyronine, glucocorticoids function as growth regulators. The functional difference of neurotransmitters and hormones through receptor subtypes can lead to differential gene expression. The functional balance of different neurotransmitters such as acetylcholine (Ach), dopamine (DA), serotonin (5-HT), norepinephrine (NE), epinephrine (EPI), glutamate and gamma amino butyric acid (GABA) and various hormones regulates the growth, division and other vital functions of a normal cell / organism.

Most neurological and psychiatric disorders involve selective or preferential impairments of neurotransmitter systems. Therefore, studies of functional neurotransmitter pathophysiology in human brain are of unique importance in view of the development of effective, mechanism-based, therapeutic modalities. The use of neurosurgically removed fresh animal tissue samples in which receptors, transporters, ion channels and enzymes essentially retain their natural environment, represents a unique experimental approach to enlarge our understanding of human brain processes. Using this experimental approach, many human brain functional proteins, in particular neurotransmitter receptors have been characterized in terms of localization, function and pharmacological properties.

Parkinson's disease, a neurological disorder involves the degeneration of dopaminergic neurons in the nigrostriatal tract, which projects from the substantia nigra pars compacta in the midbrain to the striatum and is essential for the control of movement. The disease leads to tremor, rigidity and hyperkinesias. Reports show a vulnerability of parkin gene to modification by dopamine, the principal neurotransmitter lost in Parkinson disease, suggesting a mechanism for the progressive loss of parkin function in dopaminergic neurons during aging and sporadic Parkinson disease. Recent studies from our laboratory have shown that the alterations in dopamine receptor subtypes gene expression during Parkinson’s disease were reversed by serotonin and gamma aminobutyric acid supplementation (Nandhu et al., 2009).

Epilepsy is syndrome of episodic brain dysfunction characterized by recurrent unpredictable spontaneous seizures. Temporal-lobe epilepsy is characterized by a loss of glutamate-stimulated GABA release that is secondary to a reduction in the number of GABA transporters (Matthew et al., 2002). Electrophysiological studies of human temporal-lobe epilepsy suggest that a loss of hippocampal GABA-mediated inhibition may underlie the neuronal hyperexcitability (Knowles, 1992). Glutamate or analogue excitatory amino acids are the principal excitatory neurotransmitters in the mammalian CNS, which is also involved in this disease. In the hippocampus, two different types of glutamate receptors, the N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, each linked to different classes of ion channels are coactivated on the release of glutamate from presynaptic terminals (Bekkers & Stevens, 1989). Pilocarpine treatment which is characterized by generalized convulsive status epilepticus (SE) in rodents well represents the characteristic neuropathological findings in the hippocampus of TLE patients (Paulose et al., 2006; Reas et al., 2007). Baccopa monnieri (Brahmi) is recommended in formulations for the management of a range of mental conditions including anxiety, poor cognition, lack of concentration, and epilepsy. Anti-epileptic property of the leaf extracts of Bacopa monnieri showed their regulatory role through the muscarinic, glutamate and serotonin receptor subtypes (Paulose et al., 2006; Reas et al., 2007; Amee et al., 2009)

Alzheimer's disease (AD) is an irreversible, progressive disorder in which brain cells (neurons) deteriorate, resulting in the loss of cognitive functions, primarily memory, judgment and reasoning, movement coordination, and pattern recognition. In advanced stages of the disease, all memory and mental functioning may be lost. It is the most common cause of dementia.

Patients also frequently have noncognitive symptoms, such as anxiety, depression, apathy, and psychosis that impair daily living. The condition predominantly affects the cerebral cortex and hippocampus, which lose mass and shrink (atrophy) as the disease advances. Mudher & Lovestone, (2002) reported neuronal loss or atrophy, mainly in the temporoparietal cortex along with an inflammatory response to the deposition of amyloid plaques and neurofibrillary tangles. The loss of memory is related to the loss of acetylcholinesterase (AChE) from both cholinergic and noncholinergic neurons of the diseased brain. However, AChE activity is increased around amyloid plaques. This increase in AChE is of significance for therapeutic strategies using AChE inhibitors. With no cure it sight for Alzheimer's disease, efforts are undertaken to lessen the symptoms once it is diagnosed. Glycosylation of AChE may be a useful diagnostic marker for AD (Sáez-Valero et al., 1999). There are medications that can lessen agitation, anxiety, unpredictable behavior, improve sleeping patterns, and treat depression. Evidences from our laboratory showed that maintenance of neurotransmitter and receptor subtypes balance can reduce and postpone the occurrence of neurological diseases (Paulose et al., 1998).

Apart from the central nervous system, neurotransmitters also play an important role in diseases associated with the peripheral system. Diabetes mellitus is a metabolic disorder associated with insulin deficiency, which affects the carbohydrate metabolism linked with various central and peripheral complications. The pancreatic islets are innervated by parasympathetic, sympathetic and sensory nerves. Several neurotransmitters are stored within the terminals of these nerves. The central nervous system through parasympathetic and sympathetic pathways regulates insulin secretion from pancreatic islets and maintains glucose homeostasis. An increased turnover of DA to norepinephrine has been reported in the pancreatic islets, which could damage the stimulatory effect of DA (Morgan & Montagu, 1985). NE, a stress hormone at higher concentration not only inhibited the DA uptake but also its stimulatory effect on insulin secretion in the pancreatic islets (Eswar et al., 2006). Medicinal plants are a major source for drug discovery in spite of the great development of synthetic molecules. Consequently, the uses of traditional medicinal plants extract in the treatment of various diseases have been flourished. Aegle marmelose and Costus pictus are known herbal medicine for the management of diabetes mellitus (Gireesh et al., 2008a; 2008b).

Neurons of the central nervous system are critically dependent upon a continuous supply of glucose and oxygen. The mammalian brain is exquisitely sensitive to reduction in the supply of glucose (Hypoglycemia) and oxygen (Hypoxia). Insulin regulates blood glucose levels by slowing the release of glucose by the liver and stimulating its entry into other cells. Hypoglycemia remains as the major obstacle to achieving the established benefits of intensive insulin therapy. Repeated episodes of low blood sugar causes neuronal death in brain causing disorientation and confusion, eventually progressing to seizures, partial paralysis or loss of consciousness. An increased number of glutamate receptors and the increased glutamate production will lead to glutamate excitotoxicity and neuronal degeneration which has an impact on the cognitive and memory function (Joseph et al., 2007; 2008). An alteration in dopamine D2 receptors in hippocampus was also observed from the recent studies from our laboratory (Remya et al., 2009).

Hypoxia generally refers to a lack of oxygen in any part of the body. In a neurological context, it refers to a reduction of oxygen to the brain despite adequate amounts of blood. A failure to deliver oxygen and glucose to the brain causes a cascade of abnormal events. In neuronal cells, responses to a decrease in oxygen availability or hypoxia include both facilitation and inhibition of neurotransmitter release. During experimental conditions, hypoxic rats show a change in brain adrenergic and glutaminergic receptor function resulting in abnormal behavioural pattern. Immediate glucose administration prior to oxygen supplementation was found to reduce the adverse effects of hypoxia at the molecular level (Finla et al., 2008). The oxygen availability to the infant should be made with out delay during the change over from umbilical cord to the atmospheric air. The more delay occurring will lead to neuronal death which will affect the intellectual capacity of the individual at later stages. The network usually formed in the adult is approximately 3.2 million kilometers for all the functions. If there is neuronal death the functional network will be less.

Neurotransmitter receptors are usually restricted to neuronal cells, but the signalling pathways activated by these receptors are widely distributed in both neural and non-neural cells. The role of the neurotransmitters- NE, 5-HT and their receptors using partial hepatectomised rat model has been studied in vivo for controlled cell proliferation. It is also suggested that an intact nervous system is an important component of the regulatory system for liver regeneration either through direct innervations of the liver or through indirect modulation of DNA synthesis resulting in cell proliferation. Studies from our lab have shown that serotonin can act as a potent hepatocyte co-mitogen and induce DNA synthesis in primary cultures of rat hepatocytes, which is mediated through the serotonin S2 receptors (Sudha & Paulose, 1998). GABA acts as an inhibitory signal through GABAA receptor while it acts as a co-mitogen through GABAB receptors during in vitro hepatocyte proliferation (Biju et al., 2001a; 2001b). Studies from our laboratory have shown that neurotransmitters, such as those in the pancreatic islet, can influence the synthesis and release of insulin (Mohanan et al., 2005a, b; 2006; Renuka et al., 2005; 2006; Ani et al., 2006a, b, c; Eswar et al., 2006; Balaram et al., 2008).

Spinal cord injuries are often caused by road traffic accidents, whereas fall from height is another significant cause of injury. The spinal cord contains nerve fibres which carry messages between the brain and different parts of the body. If it is damaged by different levels of shearing, one or several of the body functions are impaired and even total paraplegia. In the present scenario there is no procedure for restoring locomotor function to such individuals. Our results showed that GABA and 5HT acting through their specific receptors play a crucial role in the spinal cord regeneration in combination with bone marrow cells. There is proliferation and differentiation of cells re-establishing the connections in the injured spinal cord resulting in the functional recovery of the individual rat (Paulose et al., 2009).

Endogenous progenitor cells can be harnessed to replace neurons lost in neurodegenerative diseases but requires the development of methods to stimulate their proliferation and differentiation. Researchers are also exploring a process called trans-differentiation —“tricking” cells of the bone marrow to produce brain cells or muscle cells. Experiments are done using different neurotransmitters – serotonin and GABA with and without pluripotent bone marrow cells extracted from the same individual given to the site of damage re-established the connection and the functional recovery was observed.

Scientists are developing a number of strategies for producing dopamine neurons from human stem cells in the laboratory for transplantation into humans with Parkinson's disease. The successful generation of an unlimited supply of dopamine neurons could make neuro transplantation widely available for Parkinson's patients at some point in the future. Researchers are now examining the possibility of transplanting GABAergic neurons in the hippocampal region for the treatment of epilepsy.

Neurotransmitters + pluripotent cell infusion at site of injury

Neuronal network re- established after treatment at the damaged site

Conclusion

As the world's aged population increases, the relative effects of many disorders of the nervous system, including stroke and dementia are numerous. Increased awareness of the global effects of neurological disorders should help health care planners and the neurological community to set up appropriate priorities in research, prevention, and management of Parkinson’s disease, epilepsy and Spinal cord injured paraplegics.

Acknowledgements

Dr. C. S. Paulose thanks DAE, DBT, DST, ICMR, UGC, Govt. of India and STEC, Kerala for providing necessary facilities.

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