Clinical Implication of Heart Rate Variability in Obstructive Sleep Apnea Syndrome Patients.

UNLABELLED: Obstructive sleep apnea syndrome (OSAS) is a common disease with the prevalence of approximately 10% in general population, and this disease entity is considered to be highly related with the development of cerebrovascular and cardiovascular diseases. In the pathogenesis of cardiovascular disease, maintaining the homeostasis of autonomic nervous system (ANS) is critical. To evaluate the homeostasis of ANS, heart rate variability (HRV) is commonly used. The object of this study was to evaluate the homeostasis of ANS using the parameters of HRV and to elucidate the correlation between the parameters and apnea-hypopnea index (AHI). METHODS: Retrospective review of 806 patients was performed and 164 patients who were diagnosed as having OSAS by in-room polysomnography and met the criteria of age, sex, and body mass index were enrolled. The calculation of HRV parameters was executed using echocardiographic data from polysomnography. RESULTS: Between the control group (N = 81, AHI < 5) and OSAS patient group (N = 83, AHI > 15), standard deviation of NN (SDNN) intervals, SDNN index, HRV triangular index, very low frequency (VLF), low frequency (LF), 5-minute total power (TP), and low-frequency to high-frequency (LF/HF) ratio showed significant differences. In the correlation analysis between AHI and HRV parameters, only LF/HF ratio was proven to be significant. CONCLUSIONS: Elucidating the imbalance of ANS in OSAS patients was feasible by HRV and its parameters.

The dopamine D2 receptor regulates the development of dopaminergic neurons via extracellular signal-regulated kinase and Nurr1 activation.

Because the dopaminergic pathways in the midbrain have been closely associated with serious neuropsychiatric disorders, the elucidation of the mechanisms underlying dopaminergic neuronal development should provide some important clues for related disorders. In mice lacking the dopamine D2 receptor (D2R-/-), stereological cell counting analysis showed that the number of mesencephalic tyrosine hydroxylase (TH) cells was significantly low during ontogeny, compared with that observed in wild-type (WT) mice, thereby indicating an alteration in dopaminergic neuronal development in the absence of D2R. The results of immunohistochemical and reverse transcription-PCR analyses revealed that the expression of Nurr1, an orphan nuclear receptor, as well as Ptx3 expression, was selectively reduced in D2R-/- mice during the embryonic stage. A reporter gene assay using the Nur response element linked to the luciferase reporter gene indicated that the stimulation of D2R results in the activation of the Nurr1-mediated reporter gene. This D2R-mediated Nur response element-dependent transcriptional activity was regulated via the activation of extracellular signal-regulated kinase (ERK). Furthermore, quinpirole treatment was shown to elicit an increase in the number of TH-positive neurons, as well as the neuritic extension of TH neurons, coupled with ERK activation and Nurr1 activation in the TH-positive neurons in primary mesencephalic cultures from WT mice. However, this regulation was not detected in the D2R-/- mice. These results suggest that signaling through D2R in association with Nurr1 using ERK, plays a critical role in mesencephalic dopaminergic neuronal development.

Alpha-synuclein enhances dopamine D2 receptor signaling.

Parkinson's disease (PD) is characterized by a selective loss of dopamine-producing neurons in the substantia nigra (SN), which in turn results in dopamine depletion in the striatum, and the presence of neuronal cytoplasmic inclusions known as Lewy bodies (LBs). Alpha-synuclein is a presynaptic protein that accumulates abnormally in LBs and is seen predominantly in cases of dementia with LBs. Although the central role of alpha-synuclein in neurodegeneration has been previously demonstrated by the discovery of missense alpha-synuclein mutations in familial PD, the specific mechanism by which alpha-synuclein contributes to these diseases remains unclear. In the present study, we examined whether alpha-synuclein affects the downstream signaling of dopamine D2 receptor (D2R). In CHO cells stably transfected with D2Rs, alpha-synuclein enhanced dopamine D2-agonist-mediated inhibition of adenylate cyclase, which consequently affected its downstream cAMP-responsive element (CRE)-mediated gene transcription, while C-terminal deletion mutant of alpha-synuclein did not. Our study suggests that the alpha-synuclein enhances the dopamine-mediated intracellular signaling pathways by D2R, thus provide a possible mechanism in presynaptic regulation of the synaptic homeostasis in the dopaminergic neurotransmission.

Striatal-enriched protein tyrosine phosphatase regulates dopaminergic neuronal development via extracellular signal-regulated kinase signaling.

The striatal-enriched protein tyrosine phosphatase (STEP) is highly expressed within dopaminoceptive neurons, suggesting the possibility that STEP may interact with dopaminergic signaling. We have previously shown that signaling through dopamine D2 receptor (D2R)-mediated extracellular signal-regulated kinase (ERK) activation plays a critical role in mesencephalic dopaminergic neuronal development. Here, we investigate the role of STEP in D2R-mediated ERK signaling, especially in dopaminergic neuronal development. Analyses of developmental expression of STEP and tyrosine hydroxylase (TH) in mouse brain demonstrate that STEP- and TH-positive cells are co-localized in the substantia nigra compacta of brains of postnatal 8-day-old mice, displaying STEP expression in dopaminergic neurons at this stage. Stereological analysis demonstrates a dynamic change in the number of STEP-expressing cells from midbrain to striatum during development in WT mice and significantly decreased number of STEP-expressing cells in mice lacking D2R (D2R(-/-) mice). The knockdown of STEP expression by treatment with oligomeric STEP siRNA significantly decreased the number of mesencephalic TH cells and inhibited D2R-mediated development of dopaminergic neurons on primary mesencephalic culture from WT mice, but not in primary cultures from D2R(-/-) mice. Furthermore, knockdown of STEP expression perturbed D2R-mediated ERK signaling in dopaminergic neuronal cells from WT mice, but not from D2R(-/-) mice. These results suggest that STEP is an important mediator in the dopamine D2R-mediated activation of ERK signaling and in the regulation of dopaminergic neuronal development.