Assessment of the Neuroprotective Potential of Glucose-Regulated Heat Shock Protein in a Model of Parkinson’s Disease in Rats

Екимова, И. В.; Pazi, M. B.; Plaksina, D. V.

doi:10.1007/s11055-019-00877-y

Cited by 2 publications

(2 citation statements)

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“…Twenty-one days after the first LC or vehicle microinjection, behavior tests were p formed and then the animals were sacrificed for further immunohistochemical and b chemical analyses. In preliminary experiments [41], using motor behavior tests (sunflow seed test, Suok test, inverted horizontal grid test), we showed that double injections of µg LC in the SNpc lead to no motor dysfunction. To assess the number of surviving D neurons and their axons, brain sections were stained with antibodies against tyrosine h droxylase (TH), the marker of DA neurons.…”

Section: Grp78 Treatment Prevents Neuronal Loss In the Substantia Nig...mentioning

confidence: 90%

“…The intranasal method of GRP78 administration is informed by the in vitro data on the ability of exogenous GRP78 to penetrate living cells, translocate to the ER, and directly affect proteostasis and cell physiology [40]. Our preliminary experiments have shown that intranasal GRP78 administration helps mitigate the process of neurodegeneration in the nigrostrial system, suggesting the bioavailability of exogenous GRP78 [41]. This study aimed to develop a new neuroprotective approach to PD therapy through the intranasal administration of recombinant GRP78.…”

Section: Introductionmentioning

confidence: 99%

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Intranasal Administration of GRP78 Protein (HSPA5) Confers Neuroprotection in a Lactacystin-Induced Rat Model of Parkinson’s Disease

Pazi,

Belan,

Komarova

et al. 2024

IJMS

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The accumulation of misfolded and aggregated α-synuclein can trigger endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), leading to apoptotic cell death in patients with Parkinson’s disease (PD). As the major ER chaperone, glucose-regulated protein 78 (GRP78/BiP/HSPA5) plays a key role in UPR regulation. GRP78 overexpression can modulate the UPR, block apoptosis, and promote the survival of nigral dopamine neurons in a rat model of α-synuclein pathology. Here, we explore the therapeutic potential of intranasal exogenous GRP78 for preventing or slowing PD-like neurodegeneration in a lactacystin-induced rat model. We show that intranasally-administered GRP78 rapidly enters the substantia nigra pars compacta (SNpc) and other afflicted brain regions. It is then internalized by neurons and microglia, preventing the development of the neurodegenerative process in the nigrostriatal system. Lactacystin-induced disturbances, such as the abnormal accumulation of phosphorylated pS129-α-synuclein and activation of the pro-apoptotic GRP78/PERK/eIF2α/CHOP/caspase-3,9 signaling pathway of the UPR, are substantially reversed upon GRP78 administration. Moreover, exogenous GRP78 inhibits both microglia activation and the production of proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), via the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway in model animals. The neuroprotective and anti-inflammatory potential of exogenous GRP78 may inform the development of effective therapeutic agents for PD and other synucleinopathies.

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Section: Grp78 Treatment Prevents Neuronal Loss In the Substantia Nig...mentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%