Miodrag "Misha" Radulovacki - US grants

DESCRIPTION (provided by applicant): Sleep apnea syndrome affects at least 3% - 5% of the adult population in this country and available data suggest that significant morbidity and increased mortality result from this disorder. Despite 40 years of intensive investigation, the brainstem mechanisms responsible for, or permissive of, sleep-related apnea remain unknown. Our work to develop and characterize a rodent model of sleep-related breathing disorder makes it feasible to systematically examine the detailed brainstem mechanisms of apnea. A brainstem anatomical pathway recently has been demonstrated in which the intertrigeminal region (ITR) of the lateral pons is posited as a key regulatory site for apneic reflexes. The ITR is innervated by sensory subnuclei of the solitary tract that receive inputs from the ninth and tenth cranial nerves; each of which mediate airway-protective apneic reflexes. Moreover, the ITR sends direct projections to respiratory rhythm generating neurons in the medulla. Although the ITR thus may represent an important airway reflex integrating site, no physiological or pathophysiological role has yet been demonstrated for this region. We present novel preliminary evidence that the ITR dampens vagally-mediated reflex apnea, an effect that appears to be mediated by glutamatergic neurotransmission and may result from short term potentiation. Further, we show that focal lesions of the ITR lead to dramatically increased apnea expression during sleep. The overall goals of this proposal are 1) to identify the neural mechanisms by which the ITR modulates apneic reflexes, 2) to demonstrate the functional role of the ITR in sleep apnea genesis and 3) to establish the impact of sleep/wake state changes on ITR function. To achieve these goals, we will employ pressure microinjections to enhance and impair ITR functional activity and to test the strength of monoaminergic and cholinergic inputs on ITR function. The acute impact of these manipulations on respiratory pattern and apneic reflexes will be tested in anesthetized rats. Sustained effects following focal lesions will be tested by behavioral state and cardiorespiratory monitoring in sleeping rats. The proposed neurochemical manipulations of the ITR provide a systematic approach to define the importance of this region in modulating both reflexive and spontaneous sleep-related apnea and to identify the initial steps in the signaling pathway by which this region modulates apnea expression.

Sleep related breathing disorders (SRBD), especially obstructive sleep apnea (OSA), represent an important health problem, conferring substantial cognitive/behavioral symptoms and increased risk of motor vehicle accident, hypertension, myocardial infarction, stroke, diabetes and death on at least 3% ofthe US population. Identifying novel treatments for OSA would be of great public health significance, because fully effective and acceptable OSA treatments are lacking. A critical need remains for NIH supported, mechanistically driven proof-of-concept clinical studies to evaluate novel therapeutic strategies. Despite basic research advances regarding the pathogenesis of OSA, generally effective drug treatments have not been identified. Based on our animal and preliminary human data, we propose to test the innovative hypothesis that cannabimimetic drugs are both effective in reducing sleep apnea severity and disease modifying in protecting against cardiovascular and neurological sequelae of OSA. Project 1 will be a randomized, placebo-controlled parallel groups proof-of-concept clinical trial of dronabinol in patients with OSA. Subjects will be randomized to receive either placebo or dronabinol for a period of 6 weeks. The overarching goal will be to establish the safety, tolerability and therapeutic efficacy of dronabinol in OSA, with co-primary efficacy endpoints including: reduced in apnea/hypopnea index (AHI) and improved subjective and objective daytime alertness at the end of treatment. Secondary endpoints will include improved oxygenation, sleep quality, blood pressure control and time-on-treatments effects. Project 2 will employ anesthetized and chronically instrumented conscious behaving animals to directly test the mechanisms of dronabinol action schematized in figure 1. For example, we will characterize dronabinol's dose-dependent inhibition of afferent vagal reflexes elicited by pharmacological and mechanical stimuli. We will use CBi and CB2 antagonists to confirm the receptor targets for reduced apnea propensity and we will establish the CNS versus vagal-reflex impact of dronabinol on upper airway muscle activity during sleep. We will test the hypothesis that cannabimimetics lower blood pressure by reducing sympathetic activity. Taken together, these projects will provide critical evidence regarding the potential efficacy and mechanisms of action for cannabimimetic treatment of OSA. By providing a path toward the first viable OSA pharmacotherapeutic, the proposed studies could have a tremendous impact on clinical practice.

Sleep related breathing disorders (SRBD), especially obstructive sleep apnea (OSA), represent an important health problem, conferring substantial cognitive/behavioral symptoms and increased risk of motor vehicle accident, hypertension, myocardial infarction, stroke, diabetes and death on at least 3% ofthe US population. Identifying novel treatments for OSA would be of great public health significance, because fully effective and acceptable OSA treatments are lacking. A critical need remains for NIH supported, mechanistically driven proof-of-concept clinical studies to evaluate novel therapeutic strategies. Despite basic research advances regarding the pathogenesis of OSA, generally effective drug treatments have not been identified. Based on our animal and preliminary human data, we propose to test the innovative hypothesis that cannabimimetic drugs are both effective in reducing sleep apnea severity and disease modifying in protecting against cardiovascular and neurological sequelae of OSA. Project 1 will be a randomized, placebo-controlled parallel groups proof-of-concept clinical trial of dronabinol in patients with OSA. Subjects will be randomized to receive either placebo or dronabinol for a period of 6 weeks. The overarching goal will be to establish the safety, tolerability and therapeutic efficacy of dronabinol in OSA, with co-primary efficacy endpoints including: reduced in apnea/hypopnea index (AHI) and improved subjective and objective daytime alertness at the end of treatment. Secondary endpoints will include improved oxygenation, sleep quality, blood pressure control and time-on-treatments effects. Project 2 will employ anesthetized and chronically instrumented conscious behaving animals to directly test the mechanisms of dronabinol action schematized in figure 1. For example, we will characterize dronabinol's dose-dependent inhibition of afferent vagal reflexes elicited by pharmacological and mechanical stimuli. We will use CBi and CB2 antagonists to confirm the receptor targets for reduced apnea propensity and we will establish the CNS versus vagal-reflex impact of dronabinol on upper airway muscle activity during sleep. We will test the hypothesis that cannabimimetics lower blood pressure by reducing sympathetic activity. Taken together, these projects will provide critical evidence regarding the potential efficacy and mechanisms of action for cannabimimetic treatment of OSA. By providing a path toward the first viable OSA pharmacotherapeutic, the proposed studies could have a tremendous impact on clinical practice.