Intranasal administration of recombinant chaperone GRP78 is a promising disease-modifying treatment approach for Parkinson&rsquo;s disease and sleep restriction-associated neurodegeneration

Mariia Pazi; Irina Ekimova

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Intranasal administration of recombinant chaperone GRP78 is a promising disease-modifying treatment approach for Parkinson’s disease and sleep restriction-associated neurodegeneration

Mariia Pazi

^*,

Irina Ekimova

¹ Laboratory of comparative Thermophysiology, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Thorez 44, Saint Petersburg, 194223, Russia

Academic Editor: Thierry Besson

Published: 29 October 2025 by MDPI in The 1st International Electronic Conference on Medicinal Chemistry and Pharmaceutics session New Small molecules as drug candidates

Abstract:

Introduction: Parkinson's disease (PD) is a neurodegenerative disorder that to date remains incurable. PD is currently linked to chronic sleep restriction (SR) as these pathologies share a similar spectrum of molecular and cellular malfunctions: accumulation of aberrant proteins, neurodegeneration, neuroinflammation, activation of unfolded protein response (UPR) apoptotic branch. Development of neuroprotective strategies for PD and SR-associated neurodegeneration remains a critical issue for pharmaceutics. Prospective drug candidates should possess high bioavailability for the brain, and the ability to influence main pathogenetic mechanisms of neurodegeneration. One of the promising drug molecules is the GRP78 (HSPA5). The objective of this study was to evaluate the protective potential of recombinant GRP78 (rGRP78) administered intranasally in a PD and SR rodent models.

Methods: The work was carried out on male Wistar rats (6 months). Microinjections of the proteasome inhibitor lactacystin (LC) into substantia nigra (SN) were used to create a PD model. SR was carried out in a polyphase manner for 5 days using a swinging platform. rGRP78 was administered intranasally 4 and 24 hours after each LC microinjection and every day during SR. Control group received LC and/or GRP78 solvents. Pathomorphological and neurochemical changes were assessed by immunohistochemistry and by Western Blot. Confocal microscopy was used to assess rGRP78 bioavailability. Statistical analysis was conducted via two-factor ANOVA and Tukey post-hoc.

Results: It was proven that SR and PD share common molecular and cellular pathological mechanisms involved in neurodegeneration. It was established that intranasally administered rGRP78 is internalized by neurons and microglia in various brain structures. rGRP78 prevents development of neurodegeneration in PD and SR due to its ability to counteract (1) aS pathology; (2) apoptotic UPR branch activation; (3) microgliosis and NF-kB-induced proinflammatory changes.

Conclusion: rGRP78 is a bioavailable to the brain tissue drug that possesses a complex protective effect in neurodegenerative pathologies.

Keywords: UPR; GRP78; Parkinson’s disease; sleep restriction; lactacystin; microglia; neuroprotection; substantia nigra.

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Mariia Pazi

Irina Ekimova