Roles of the orexin system in central motor control

Hu, Bo; Yang, Ning; Qiao, Qi‐Cheng; Hu, Zhian; Zhang, Jun

doi:10.1016/j.neubiorev.2014.12.005

Cited by 53 publications

(51 citation statements)

References 137 publications

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“…28 It is clear from the present results that almorexant reduces the heightened locomotor activity in BPH/2J mice, which could reflect the effect of orexin on neuronal regulation of motor activity 29 or promotion of sleep, 30 both of which can influence BP. 31,32 Thus, an important question is whether the hypotensive effect of almorexant in BPH/2J mice is dependent on reductions in locomotor activity.…”

Section: Effect Of Sleep/locomotionmentioning

confidence: 68%

Contribution of Orexin to the Neurogenic Hypertension in BPH/2J Mice

et al. 2016

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BPH/2J mice are a genetic model of hypertension which were selectively bred for elevated blood pressure (BP) in the 1970s alongside a normotensive strain (BPN/3J).1 Recent studies suggest that the hypertension in BPH/2J mice is caused by enhanced activation of the sympathetic nervous system (SNS) because ganglion blockade causes a greater depressor response in BPH/2J mice compared with BPN/3J controls. 2,3 Importantly, cardiovascular regulatory forebrain regions within the hypothalamus and amygdala display markedly greater neuronal activity in BPH/2J compared with BPN/3J mice during the dark-active period of the 24-hour light cycle.2 Furthermore, lesions of the medial amygdala reduced the hypertension and SNS overactivity in BPH/2J mice. 4 Thus the central nervous system seems to play a crucial role in driving the sympathetically mediated hypertension in this model.A gene array approach has been used to identify differential expression of genes in the hypothalamus between BPH/2J and BPN/3J mice. 5,6 An important finding was that expression of the orexin precursor gene (hcrt) in BPH/2J mice was more than double that of normotensive mice in early and established hypertension. Thus, hcrt could potentially contribute to the development and maintenance of BPH/2J hypertension.5 Furthermore, BPH/2J mice have ≈4-fold greater expression of the hcrt gene in the hypothalamus during the dark-active period compared with light period when mice are predominantly inactive or asleep. 6 Characteristics of the BPH/2J mouse strain, such as high BP, tachycardia, greater locomotor activity, overactivity of the SNS, 2 and exaggerated cardiovascular reactivity to stressful stimuli, 7 could all be reflective of a greater activity of the orexinergic neurons. Indeed, orexin is capable of increasing BP, heart rate (HR), and SNS activity.8 Orexinergic neurons originate in the hypothalamus and project to a wide range of brain regions, but in terms of sympathetic control of BP, the Abstract-BPH/2J mice are a genetic model of hypertension associated with an overactive sympathetic nervous system.Orexin is a neuropeptide which influences sympathetic activity and blood pressure. Orexin precursor mRNA expression is greater in hypothalamic tissue of BPH/2J compared with normotensive BPN/3J mice. To determine whether enhanced orexinergic signaling contributes to the hypertension, BPH/2J and BPN/3J mice were preimplanted with radiotelemetry probes to compare blood pressure 1 hour before and 5 hours after administration of almorexant, an orexin receptor antagonist. Mid frequency mean arterial pressure power and the depressor response to ganglion blockade were also used as indicators of sympathetic nervous system activity. Administration of almorexant at 100 (IP) and 300 mg/ kg (oral) in BPH/2J mice during the dark-active period (2 hours after lights off) markedly reduced blood pressure (−16.1±1.6 and −11.0±1.1 mm Hg, respectively; P<0.001 compared with vehicle). However, when almorexant (100 mg/ kg, IP) was administered during the light-inactive pe...

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Section: Effect Of Sleep/locomotionmentioning

confidence: 68%

Contribution of Orexin to the Neurogenic Hypertension in BPH/2J Mice

et al. 2016

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“…However, it appears that neurons in the DMV, gigantocellular reticular nucleus, dorsal and median RN, LC, LH, PPN, basal forebrain and ILT all have large, diffuse axonal projections to varying degrees, distinguishing them from the vast majority of sensory or motor neurons in the brain, which typically have spatially focused, modestly branched axons that conform to topographic maps [100,101,102,103,104,105,106,107]…”

Section: A Common At-risk Neuronal Phenotype In Pd?mentioning

confidence: 99%

Calcium and Parkinson's disease

Surmeier

Schumacker

Guzmán

et al. 2017

Biochemical and Biophysical Research Communications

169

146

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Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world. Its causes are poorly understood and there is no proven therapeutic strategy for slowing disease progression. The core motor symptoms of PD are caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). In these neurons, Ca2+entry through plasma membrane Cav1 channels drives a sustained feed-forward stimulation of mitochondrial oxidative phosphorylation. Although this design helps prevent bioenergetic failure when activity needs to be sustained, it leads to basal mitochondrial oxidant stress. Over decades, this basal oxidant stress could compromise mitochondrial function and increase mitophagy, resulting in increased vulnerability to other proteostatic stressors, like elevated alpha synuclein expression. Because this feedforward mechanism is no longer demanded by our lifestyle, it could be dispensed with. Indeed, use of dihydropyridines – negative allosteric modulators of Cav1 Ca2+ channels – comes with little or no effect on brain function but is associated with decreased risk and progression of PD. An ongoing, NIH sponsored, Phase 3 clinical trial in North America is testing the ability of one member of the dihydropyridine class (isradipine) to slow PD progression in early stage patients. The review summarizes the rationale for the trial and outlines some unanswered questions.

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“…For example, SNc DA neurons in the rodent have axons that branch profusely in the striatum and possess as many as 200,000 vesicular release sites (Matsuda et al, 2009). Although less well characterized, neurons in the DMV, GCN, RN, LC, PPN, BFN, LH and ILN all share this feature (large, diffuse axonal projections) to varying degrees, distinguishing them from the vast majority of sensory or motor neurons in the brain, which typically have spatially focused, modestly branched axons that conform to topographic maps (Aston-Jones and Waterhouse, 2016; Baufreton et al, 2009; Hornung, 2003; Hu et al, 2015; Liu et al, 2015; Martinez-Gonzalez et al, 2011; Pfaff et al, 2012; Ratcliffe et al, 2011). Why might a long and highly branched axon increase vulnerability?…”

Section: The Rationale For a Cav1 Ca2+ Channel Inhibitormentioning

confidence: 99%

Calcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease

Surmeier

Halliday

Simuni

2017

Experimental Neurology

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Parkinson’s disease is characterized by progressively distributed Lewy pathology and neurodegeneration. The motor symptoms of cPD are unequivocally linked to the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Several features of these neurons appear to make them selectively vulnerable to factors thought to cause cPD, like aging, genetic mutations and environmental toxins. Among these features, Ca2+ entry through Cav1 channels is particularly amenable to pharmacotherapy in early stage cPD patients. This review outlines the linkage between these channels, mitochondrial oxidant stress and cPD pathogenesis. It also summarizes considerations that went into the design and execution of the ongoing Phase 3 clinical trial with an inhibitor of these channels – isradipine.

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Roles of the orexin system in central motor control

Cited by 53 publications

References 137 publications

Contribution of Orexin to the Neurogenic Hypertension in BPH/2J Mice

Contribution of Orexin to the Neurogenic Hypertension in BPH/2J Mice

Calcium and Parkinson's disease

Calcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease

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