Effects of long-term hypoxia on tyrosine hydroxylase protein content in catecholaminergic rat brainstem areas: a quantitative autoradiographic study

Pépin, Jean‐Louis; Lévy, Patrick; Garcin, Aurélie; Feuerstein, Claude; Savasta, Marc

doi:10.1016/0006-8993(96)00250-8

Cited by 21 publications

(12 citation statements)

References 30 publications

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“…Chronic sustained hypoxia causes elevation of tyrosine hydroxylase expression and activity in selected brain regions (Pépin et al, 1996; Gozal et al, 2005). In contrast, following CIH, despite the evidence for increase sympathetic activation and increased circulating catecholamine/angiotensin II levels, brain tyrosine hydroxylase levels and activity are minimally affected (Li et al, 1996; Gozal et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Glucoregulatory Consequences and Cardiorespiratory Parameters in Rats Exposed to Chronic–Intermittent Hypoxia: Effects of the Duration of Exposure and Losartan

Fenik¹,

Singletary²,

Branconi³

et al. 2012

Front. Neur.

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Background: Obstructive sleep apnea (OSA) is associated with glucose intolerance. Both chronic sleep disruption and recurrent blood oxygen desaturations (chronic–intermittent hypoxia, CIH) may cause, or exacerbate, metabolic derangements. Methods: To assess the impact of CIH alone, without accompanying upper airway obstructions, on the counter-regulatory response to glucose load and cardiorespiratory parameters, we exposed adult male Sprague-Dawley rats to CIH or sham room air exchanges for 10 h/day for 7, 21, or 35 days and then, 1 day after conclusion of CIH exposure, conducted intravenous glucose-tolerance tests (ivgtt) under urethane anesthesia. Additional rats underwent 35 days of CIH followed by 35 days of regular housing, or had 35 day-long CIH exposure combined with daily administration of the type 1 angiotensin II receptor antagonist, losartan (15 mg/kg, p.o.), and then were also subjected to ivgtt. Results: Compared with the corresponding control groups, CIH rats had progressively reduced glucose-stimulated insulin release and impaired glucose clearance, only mildly elevated heart rate and/or arterial blood pressure and slightly reduced respiratory rate. The differences in insulin release between the CIH and sham-treated rats disappeared in the rats normally housed for 35 days after 35 days of CIH/sham exposure. The losartan-treated rats had improved insulin sensitivity, with no evidence of suppressed insulin release in the CIH group. Conclusion: In adult rats, the glucose-stimulated insulin release is gradually suppressed with the duration of exposure to CIH, but the effect is reversible. Elimination of the detrimental effect of CIH on insulin release by losartan suggests that CIH disrupts glucoregulation through angiotensin/catecholaminergic pathways. Accordingly, treatment with continuous positive airway pressure may ameliorate pre-diabetic conditions in OSA patients, in part, by reducing sympathoexcitatory effects of recurrent nocturnal hypoxia.

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Section: Discussionmentioning

confidence: 99%

Glucoregulatory Consequences and Cardiorespiratory Parameters in Rats Exposed to Chronic–Intermittent Hypoxia: Effects of the Duration of Exposure and Losartan

Fenik¹,

Singletary²,

Branconi³

et al. 2012

Front. Neur.

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“…TH activity in each tissue was expressed as picomoles per milligram protein of L-DOPA formed during 20 min. Neurochemical determination of L-DOPA tissue content was performed using HPLC as previously described, and L-DOPA accumulation was expressed as picomoles per milligram protein per 20 min (23)(24)(25).…”

Section: Chronic Intermittent Hypoxia Exposuresmentioning

confidence: 99%

Intermittent Hypoxia during Development Induces Long-Term Alterations in Spatial Working Memory, Monoamines, and Dendritic Branching in Rat Frontal Cortex

et al. 2005

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Exposure to intermittent hypoxia (IH), such as occurs in sleep-disordered breathing, is associated with increased apoptosis in vulnerable brain regions as well as with spatial reference memory deficits in adult and developing rats. The latter are more susceptible to IH, suggesting that early exposure to IH may have long-term consequences. Rats were exposed to 14 d of room air (RA) or IH starting at postnatal d 10. Working memory was then assessed in the water maze at 4 mo of age using a delayed matching to place task in which the rats were required to locate a submerged platform hidden in a novel location on the first trial (T1 or acquisition trial), and then remember that position after a delay (T2 or test trial). Mean escape latencies and swim distances were derived and the savings (T1-T2) were used as a measure of working memory. Male but not female rats exposed to IH showed working memory deficits at both a 10-and 120-min delay (for both latency and pathlength). Additionally, Sholl analysis of Golgi-stained neurons revealed decreased dendritic branching in the frontal cortex, but not the hippocampus, of male rats exposed to IH. Norepinephrine concentrations, dopamine turnover, and tyrosine hydroxylase activity were increased similarly in males and females. However, increased dopamine concentrations were present only in the frontal cortex of female rats. In conclusion, exposure to IH during a critical developmental period is associated with long-term alterations in frontal cortical dopaminergic pathways that may underlie gender differences in neurobehavioral deficits. OSA is a highly prevalent condition that affects 2-3% of all children (1-3). It is characterized by the repetitive development of either complete or partial upper airway occlusion that leads to periodic hypoxemia and hypercapnia and to recurring arousals. In recent years, it has become apparent that OSA imposes substantial neurobehavioral morbidity (4 -6), particularly of functions pertaining to the PFC (7), and that such alterations in attention, executive, and intellectual function may not be completely reversible (8). The recent development of a rodent model, whereby IH is applied during sleep, has allowed for improved delineation of some of the potential mechanisms underlying the morbid consequences of OSA (8 -17). Furthermore, a unique period of neuronal susceptibility emerged, such that developing rats exposed to IH displayed reduced apoptosis during the immediate postnatal period but markedly enhanced neuronal cell loss between 10 and 25 d of age, compared with adult animals (18). Furthermore, exposure to IH during this period was associated with marked reductions in the ability to acquire a spatial task in the water maze and with locomotor hyperactivity in males but not in females (9). The potential irreversibility of the IH-induced effects was further suggested by Decker and colleagues (19), who reported altered dopaminergic transmission in rats exposed perinatally

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“…Chronic sustained hypoxia increased TH activity in the brainstem which was primarily attributed to upregulation of TH protein (42,46). On the other hand, studies in PC12 cells (27) showed that IH-induced increase in TH activity is not associated with a concomitant increase in TH protein, suggesting IH-induced TH activation.…”

Section: Introductionmentioning

confidence: 96%

Pattern-Specific Sustained Activation of Tyrosine Hydroxylase by Intermittent Hypoxia: Role of Reactive Oxygen Species-Dependent Downregulation of Protein Phosphatase 2A and Upregulation of Protein Kinases

Raghuraman

Rai

Peng

et al. 2009

Antioxidants & Redox Signaling

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We investigated the role of protein phosphatases (PP) and protein kinases in tyrosine hydroxylase (TH) activation by two patterns of intermittent hypoxia (IH) in rat brainstem. Rats exposed to either IH(15s) (15 s, 5% O(2); 5 min, 21%O(2)) or IH(90s) (90 s each of 10% O(2) & 21%O(2)) for 10 days were used. IH(15s) but not IH(90s) caused a robust increase in TH activity, dopamine (DA) level, and TH phosphorylation at Ser-31 and Ser-40 in the medulla but not in the pons. Likewise, IH(15s) but not IH(90s) decreased activity and expression of protein phosphatase 2A (PP2A) and increased activity of multiple protein kinases. In vitro dephosphorylation with PP2A nearly abolished IH(15s)-induced increase in TH activity. IH(15s) increased generation of reactive oxygen species (ROS) in brainstem medullary regions which was nearly threefold higher than that evoked by IH(90s). Antioxidants prevented IH(15s)-induced downregulation of PP2A and increases in multiple protein kinase activity with subsequent reversal of serine phosphorylation of TH, TH activity, and DA to control levels. These findings demonstrate that IH in a pattern-specific manner activates TH involving ROS-mediated sustained increase in TH phosphorylation via downregulation of PP2A and upregulation of protein kinases.

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Effects of long-term hypoxia on tyrosine hydroxylase protein content in catecholaminergic rat brainstem areas: a quantitative autoradiographic study

Cited by 21 publications

References 30 publications

Glucoregulatory Consequences and Cardiorespiratory Parameters in Rats Exposed to Chronic–Intermittent Hypoxia: Effects of the Duration of Exposure and Losartan

Glucoregulatory Consequences and Cardiorespiratory Parameters in Rats Exposed to Chronic–Intermittent Hypoxia: Effects of the Duration of Exposure and Losartan

Intermittent Hypoxia during Development Induces Long-Term Alterations in Spatial Working Memory, Monoamines, and Dendritic Branching in Rat Frontal Cortex

Pattern-Specific Sustained Activation of Tyrosine Hydroxylase by Intermittent Hypoxia: Role of Reactive Oxygen Species-Dependent Downregulation of Protein Phosphatase 2A and Upregulation of Protein Kinases

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