Heat Shock Proteins and Autophagy Pathways in Neuroprotection: From Molecular Bases to Pharmacological Interventions

Penke, Botond; Bogár, Ferenc; Crul, Tim; Sántha, Miklós; Tóth, Melinda E.; Vı́gh, László

doi:10.3390/ijms19010325

Cited by 76 publications

(53 citation statements)

References 325 publications

(382 reference statements)

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“…Overall, previous data (Kasza et al, 2016;Penke et al, 2018;Roe et al, 2018) and those of ours together suggest that LA1011 may be considered to counteract neurodegeneration, with no major, concomitant impact on vascular tone or neurovascular coupling. Furthermore, the work demonstrates that L-type voltage-gated calcium channel inhibition augments functional hyperaemia in response to somatosensory stimulation especially under ischaemia, in addition to achieving a general, constitutive vasodilator effect.…”

Section: Discussionsupporting

confidence: 78%

“…A more detailed understanding of the molecular pathways involved either in LA1011 or in nimodipine action assessed here requires further investigation. Overall, previous data (Kasza et al, 2016;Penke et al, 2018;Roe et al, 2018) and those of ours together suggest that LA1011 may be considered to counteract neurodegeneration, with no major, concomitant impact on vascular tone or neurovascular coupling. ORCID Eszter Farkas https://orcid.org/0000-0002-8478-9664…”

Section: Discussionsupporting

confidence: 78%

“…One of these promising novel compounds is LA1011 (dimethyl 4-(4-trifluoromethylphenyl)-2,6-bis-(2-dimethylaminoethyl)-1-methyl-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride), which is known as a co-inducer of heat shock protein (Hsp; especially Hsp27 and Hsp70) with no affinity for calcium channels (Kasza et al, 2016). Long-term administration of LA1011 was shown to improve learning ability, counteract neuronal loss, increase dendritic spine density, and restrain tau pathology and amyloid plaque formation in a transgenic mouse model of Alzheimer's disease (Kasza et al, 2016), possibly by maintaining protein homeostasis (Penke et al, 2018). Taken that Hsp27 and Hsp70 activation has been suggested to be protective against ischaemic neurodegeneration (Kim, Han, Lee, & Yenari, 2018;van der Weerd et al, 2010;Yenari et al, 2005), it is of interest whether LA1011, a co-inducer of Hsp, has the potential to preserve neuronal function under cerebral ischaemia.…”

Section: Introductionmentioning

confidence: 99%

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The impact of dihydropyridine derivatives on the cerebral blood flow response to somatosensory stimulation and spreading depolarization

Szabó

Tóth

Török

et al. 2019

British J Pharmacology

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Background and Purpose: A new class of dihydropyridine derivatives, which act as co-inducers of heat shock protein but are devoid of calcium channel antagonist and vasodilator effects, has recently been developed with the purpose of selectively targeting neurodegeneration. Here, we evaluated the action of one of these novel compounds LA1011 on neurovascular coupling in the ischaemic rat cerebral cortex.As a reference, we applied nimodipine, a vasodilator dihydropyridine and wellknown calcium channel antagonist.Experimental Approach: Rats were treated with LA1011 or nimodipine, either by chronic, systemic (LA1011), or acute, local administration (LA1011 and nimodipine).In the latter treatment group, global forebrain ischaemia was induced in half of the animals by bilateral common carotid artery occlusion under isoflurane anaesthesia.Functional hyperaemia in the somatosensory cortex was created by mechanical stimulation of the contralateral whisker pad under α-chloralose anaesthesia. Spreading depolarization (SD) events were elicited subsequently by 1 M KCl. Local field potential and cerebral blood flow (CBF) in the parietal somatosensory cortex were monitored by electrophysiology and laser Doppler flowmetry.Key Results: LA1011 did not alter CBF, but intensified SD, presumably indicating the co-induction of heat shock proteins, and, perhaps an anti-inflammatory effect.Nimodipine attenuated evoked potentials and SD. In addition to the elevation of baseline CBF, nimodipine augmented hyperaemia in response to both somatosensory stimulation and SD, particularly under ischaemia. Conclusions and implications:In contrast to the CBF improvement achieved with nimodipine, LA1011 seems not to have discernible cerebrovascular effects but may up-regulate the stress response.Abbreviations: 2VO, permanent, bilateral occlusion of the common carotid arteries ("two-vessel occlusion"); CBF, cerebral blood flow; DC, direct current; EFP, evoked field potential; eNOS, endothelial NOS; Hsp, heat shock protein; LDF, laser Doppler flowmetry; LFP, local field potential; MABP, mean arterial BP; rSD, recurrent spreading depolarization; SD, spreading depolarization; SD1, the first spreading depolarization in a train of events

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Section: Discussionsupporting

confidence: 78%

Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The impact of dihydropyridine derivatives on the cerebral blood flow response to somatosensory stimulation and spreading depolarization

Szabó

Tóth

Török

et al. 2019

British J Pharmacology

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“…UPR works in concert with endoplasmic reticulum‐associated degradation that directs unfolded proteins for destruction by the ubiquitin–proteasome system (UPS) (Penke et al . ). Failure of the UPR to keep up this screening mechanism leads to the buildup of misfolded proteins in the ER which accumulate in mitochondria‐associated ER membranes and cause mitochondrial dysfunction (Schon and Area‐Gomez ; Volgyi et al .…”

Section: Redox Proteomics and Aβ(1–42)‐mediated Oxidative Stress In Tmentioning

confidence: 97%

Redox proteomics and amyloid β‐peptide: insights into Alzheimer disease

Butterfield

Boyd‐Kimball

2018

Journal of Neurochemistry

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Alzheimer disease (AD) is a progressive neurodegenerative disorder associated with aging and characterized pathologically by the presence of senile plaques, neurofibrillary tangles, and neurite and synapse loss. Amyloid beta-peptide (1-42) [Aβ(1-42)], a major component of senile plaques, is neurotoxic and induces oxidative stress in vitro and in vivo. Redox proteomics has been used to identify proteins oxidatively modified by Aβ(1-42) in vitro and in vivo. In this review, we discuss these proteins in the context of those identified to be oxidatively modified in animal models of AD, and human studies including familial AD, pre-clinical AD (PCAD), mild cognitive impairment (MCI), early AD, late AD, Down syndrome (DS), and DS with AD (DS/AD). These redox proteomics studies indicate that Aβ(1-42)-mediated oxidative stress occurs early in AD pathogenesis and results in altered antioxidant and cellular detoxification defenses, decreased energy yielding metabolism and mitochondrial dysfunction, excitotoxicity, loss of synaptic plasticity and cell structure, neuroinflammation, impaired protein folding and degradation, and altered signal transduction. Improved access to biomarker imaging and the identification of lifestyle interventions or treatments to reduce Aβ production could be beneficial in preventing or delaying the progression of AD. This article is part of the Proteomics special issue.

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“…Noise may drive a protein expression program to delete or refold damaged proteins that could impair cellular functions. Heat shock proteins are involved in various aspects of signal transduction, protein folding, and degradation, apoptosis, and inflammation (30). Two major protein networks were identified in TTS and PTS but not NTA conditions, Arp2/3 complex and the Ubiquinol-Cytochrome C reductase complex (Fig.…”

Section: Resultsmentioning

confidence: 99%