Induction of the 27-kDa Heat Shock Protein (Hsp27) in the Rat Medulla Oblongata after Vagus Nerve Injury

doi:10.1006/exnr.1998.6870

Experimental Neurology

Volume 153, Issue 2, October 1998, Pages 173-183

https://doi.org/10.1006/exnr.1998.6870 Get rights and content

Abstract

The 27-kDa heat shock protein (Hsp27) is constitutively expressed in motor and sensory neurons of the brainstem. Hsp27 is also rapidly induced in the nervous system following oxidative and cellular metabolic stress. In this study, we examined the distribution of Hsp27 in the rat medulla oblongata by means of immunohistochemistry after the vagus nerve was cut or crushed. After vagal injury, rats were allowed to survive for 6, 12, 24 h, 2, 4, 7, 10, 14, 30, or 90 days. Vagus nerve lesions resulted in a time-dependent up-regulation of Hsp27 in vagal motor and nodose ganglion sensory neurons that expressed Hsp27 constitutively andde novoinduction in neurons that did not express Hsp27 constitutively. In the dorsal motor nucleus of the vagus nerve (DMV) and nucleus ambiguus, the levels of Hsp27 in motor neurons were elevated within 24 h of injury and persisted for up to 90 days. Vagal afferents to the nucleus of the tractus solitarius (NTS) and area postrema showed increases in Hsp27 levels within 4 days that were still present 90 days postinjury. In addition, increases in Hsp27 staining of axons in the NTS and DMV suggest that vagus nerve injury resulted in sprouting of afferent axons and spread into areas of the dorsal vagal complex not normally innervated by the vagus. Our observations are consistent with the possibility that Hsp27 plays a role in long-term survival of distinct subpopulations of injured vagal motor and sensory neurons.

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Rat vagus nerve stimulation model of seizure suppression: nNOS and ΔFos B changes in the brainstem
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Citation Excerpt :
Evidence shows that the vagus nerve is very sensitive to injury, either by transection, crush, or mild manipulation, all of which can result in changes in expression of nNOS and the 27-kDA heat shock protein Hsp27 (a protein that is rapidly induced following oxidative and cellular metabolic stress (Hopkins et al., 1998; Krueger-Naug et al., 2000). Vagus nerve lesion studies have revealed that increased nNOS expression occurs in vagal motoneurons between 2 and at least 40 days after lesioning the nerve (Hopkins et al., 1996; Ji et al., 2002) while changes in the expression of Hsp27 persist for up to 90 days after vagus nerve injury (Hopkins et al., 1998). Moreover, El Tahry et al. (2011) recently reported that 50% of animals that had received a vagus nerve electrode displayed diminished larynx compound muscle potentials for about 4 weeks after surgery.
Vagus nerve stimulation (VNS) is a moderately effective treatment for intractable epilepsy. However, the mechanism of action is poorly understood. The effect of left VNS in amygdala kindled rats was investigated by studying changes in nNOS and ΔFos B expression in primary and secondary vagus nerve projection nuclei: the nucleus of the solitary tract (NTS), dorsal motor nucleus of the vagus nerve (DMV), parabrachial nucleus (PBN) and locus coeruleus (LC).
Rats were fully kindled by stimulation of the amygdala. Subsequently, when the fully kindled state was reached and then maintained for ten days, rats received a single 3-min train of VNS starting 1 min prior to the kindling stimulus and lasting for 2 min afterwards. In control animals the vagus nerve was not stimulated. Animals were sacrificed 48 h later. The brainstems were stained for neuronal nitric oxide synthase (nNOS) and ΔFos B.
VNS decreased seizure duration with more than 25% in 21% of rats. No VNS associated changes in nNOS immunoreactivity were observed in the NTS and no changes in ΔFos B were observed in the NTS, PBN, or LC. High nNOS immunopositive cell densities of >300 cells/mm² were significantly more frequent in the left DMV than in the right (χ²(1) = 26.2, p < 0.01), independent of whether the vagus nerve was stimulated.
We conclude that the observed nNOS immunoreactivity in the DMV suggests surgery-induced axonal damage. A 3-min train of VNS in fully kindled rats does not affect ΔFos B expression in primary and secondary projection nuclei of the vagus nerve.
Neuroprotective effect on retinal ganglion cells by transpupillary laser irradiation of the optic nerve head
2010, Neuroscience Letters
This study demonstrates that subthreshold transpupillary thermotherapy (TTT) laser irradiation on optic nerve head protects retinal ganglion cells (RGCs) in an optic nerve crush (ONC) model. TTT was performed in right eyes with an 810-nm diode laser aimed at the center of the optic nerve head, using the following protocol: power 60 mW, duration 60 s, spot size 500 μm. Fluoro-Gold was injected into bilateral superior colliculi 5 days before sacrifice and fluorescent gold labeled RGCs were counted under fluorescence microscopy. In the ONC group, a progressive loss of RGCs was observed; however, in comparison with the ONC group, RGCs density was significantly higher (P = 0.001, independent samples t-test) at day 7 postoperative and only borderline significances were obtained at days 14 and 28 postoperative (P = 0.044 and P = 0.045, respectively, independent samples t-test) in ONC + TTT group, which implies the potential neuroprotective role of TTT. This protective effect seems to be heat shock proteins (HSPs) related, because intraperitoneal Quercetin (an inhibitor of HSPs, 4 mg/kg/day for 7 days) could completely abolish this protective effect at days 7, 14 and 28 postoperative (P = 0.012, P = 0.002, and P = 0.000, respectively, independent samples t-test). Minimal collateral damage of TTT on optic nerve head tissue, peripapillary RGCs and the myelin sheath of the optic nerve were observed under transmission electron microscopy. These findings suggested that subthreshold TTT might be a safe and practical approach to protect RGCs. The underlying mechanisms may involve TTT-induced HSPs in RGCs.
Acute seizure-suppressing effect of vagus nerve stimulation in the amygdala kindled rat
2010, Brain Research
Purpose: Vagus nerve stimulation (VNS) is a moderately effective anti-epileptic treatment. Clinically relevant animal models that are suitable to study the mechanism of action of VNS are not available. The aim of the current study was to develop a clinically relevant animal model for VNS-treated epilepsy that can be used to study the mechanism of action of VNS. Methods: The anticonvulsive effect of VNS was studied in fully kindled rats by measuring behavioral and electrophysiological parameters. Afferent vagus nerve activation was confirmed by quantifying nNOS immunoreactive cells in the nucleus of the solitary tract (NTS). Results: VNS rats had more nNOS immunoreactive cells/mm² in the NTS than shams. VNS induced a > 25% decrease in stage 5 duration (S5D) in 32% of rats. Prior to VNS this type of responders suffered from seizures with a longer total seizure duration (TSD) than non-responders. In 21% of rats VNS resulted in a > 25% decrease in TSD. This type of responders had a shorter TSD prior to VNS than non-responders. In 29% of rats VNS resulted in > 200% increase in stage 5 latency (S5L). This type of responders had higher kindling rates than non-responders. Conclusion: The VNS-treated kindled rat is a clinically relevant animal model because it is a chronic epilepsy model that responds to VNS with effects that are comparable to the effects of VNS in epilepsy patients. In addition, this study demonstrates that VNS-treated kindled rats can be used to study the mode of action of VNS using immunohistochemical techniques.
Heat shock protein 27 in neuronal survival and neurite outgrowth
2009, Biochemical and Biophysical Research Communications
The small heat shock protein 27 (Hsp27) is well documented to promote neuronal survival in neurodegenerative diseases and following nerve injury. It can directly inhibit apoptotic pathways, and as a chaperone it can ameliorate the toxic effects of misfolded proteins. More recently, Hsp27 has been implicated to also play a role in neurite outgrowth. Thus, Hsp27 is situated at the intersection of neuronal survival and differentiation and, as such, it has dual potential as a key therapeutic target for neuroregeneration.
Phosphorylated tau and the neurodegenerative foldopathies
2005, Biochimica et Biophysica Acta - Molecular Basis of Disease
Many studies have implicated phosphorylated tau in the Alzheimer disease process. However, the cellular fate of phosphorylated tau has only recently been described. Recent work has shown that tau phosphorylation at substrate sites for the kinases Cdk5 and GSK3-beta can trigger the binding of tau to the chaperones Hsc70 and Hsp27. The binding of phosphorylated tau to Hsc70 implied that the complex may be a substrate for the E3 ligase CHIP and this possibility was experimentally verified. The presence of this system in cells suggests that phosphorylated tau may hold toxic dangers for cell viability, and the response of the cell is to harness a variety of protective mechanisms. These include binding to chaperones, which may prevent more toxic conformations of the protein, ubiquitination which will direct the protein to the proteasome, segregation of tau aggregates from the cellular machinery, and recruitment of Hsp27 which will confer anti-apoptotic properties to the cell.
Binding of Tau to Heat Shock Protein 27 Leads to Decreased Concentration of Hyperphosphorylated Tau and Enhanced Cell Survival
2004, Journal of Biological Chemistry
Pathological hyperphosphorylated tau is the principal component of paired helical filaments, a pathological hallmark of Alzheimer disease (AD) and a strong candidate for a neurotoxic role in AD and other neurodegenerative disorders. Here we show that heat shock protein 27 (Hsp27) preferentially binds pathological hyperphosphorylated tau and paired helical filaments tau directly but not non-phosphorylated tau. The formation of this complex altered the conformation of pathological hyperphosphorylated tau and reduced its concentration by facilitating its degradation and dephosphorylation. Moreover, Hsp27 rescues pathological hyperphosphorylated tau-mediated cell death. Therefore, Hsp27 is likely to provide a neuroprotective effect in AD and other tauopathies.

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^☆: R. I. MorimotoA. TissièresC. Georgopoulos

¹: Present address: Dr. J.-Christophe Plumier, Centre de Recherche de l'Hotel-Dieu, Université Laval, 11 Côte du Palais, Québec, Québec G1R 2J6.

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Regular ArticleInduction of the 27-kDa Heat Shock Protein (Hsp27) in the Rat Medulla Oblongata after Vagus Nerve Injury☆

Abstract

Brain Res. Bull.

Neuroscience

Brain Res. Bull.

Prog. Brain Res.

Trends Biochem. Sci.

J. Biol. Chem.

Brain Res.

J. Biol. Chem.

Brain Res. Bull.

J. Biol. Chem.

Neuroscience

Mol. Brain Res.

Mol. Brain Res.

Mol. Brain Res.

Axon reaction in dorsal motor vagal and hypoglossal neurons of the adult rat. Light microscopy and RNA-cytochemistry

J. Comp. Neurol.

Viscerotopic representation of the upper alimentary tract in the rat: Sensory ganglia and nuclei of the solitary and spinal trigeminal tracts

J. Comp. Neurol.

Expression and function of the low-molecular-weight heat shock proteins

The Biology of Heat Shock Proteins and Molecular Chaperones

Viscerotopic representation of the upper alimentary tract in the medulla oblongata in the rat: The nucleus ambiguus

J. Comp. Neurol.

Time course of degenerative and regenerative changes in the dorsal horn in a rat model of peripheral neuropathy

J. Comp. Neurol.

Enhanced constitutive expression of the 27-kDa heat shock proteins in heat-resistant variants from Chinese hamster cells

J. Cell Physiol.

Axonal transport of a heat shock protein in the rabbit visual system

Proc. Nat. Acad. Sci. USA

Morphology of identified preganglionic neurons in the dorsal motor nucleus of the vagus

J. Comp. Neurol.

Development and tissue-specific distribution of mouse small heat shock protein hsp25

Dev. Genet.

Long-lasting expression of JUN and KROX transcription factors and nitric oxide synthase in intrinsic neurons of the rat brain following axotomy

J. Neurosci.

Cardiorespiratory neurons in the medulla oblongata: Input and output relationships

Induction of the 27-kDa heat shock protein (Hsp27) and nitric oxide synthase (NOS) in the rat medulla oblongata after vagotomy

Soc. Neurosci. Abstr.

Exogenous heat shock cognate protein Hsc70 prevents axotomy-induced death of spinal sensory neurons

Cell Stress Chaperones

Regular Article
Induction of the 27-kDa Heat Shock Protein (Hsp27) in the Rat Medulla Oblongata after Vagus Nerve Injury☆