"Sigma-1 receptor modulation by clemastine highlights its repurposing as neuroprotective agent against seizures and cognitive deficits in PTZ-kindled rats".

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  • Additional Information
    • Source:
      Publisher: Elsevier Science Country of Publication: Netherlands NLM ID: 1254354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0712 (Electronic) Linking ISSN: 00142999 NLM ISO Abbreviation: Eur J Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: 2005- : Amsterdam : Elsevier Science
      Original Publication: Amsterdam, North Holland Pub. Co.
    • Subject Terms:
      Receptors, sigma*/metabolism ; Receptors, sigma*/agonists ; Sigma-1 Receptor* ; Neuroprotective Agents*/pharmacology ; Neuroprotective Agents*/therapeutic use ; Seizures*/drug therapy ; Seizures*/metabolism ; Cognitive Dysfunction*/drug therapy ; Cognitive Dysfunction*/metabolism ; Cognitive Dysfunction*/prevention & control ; Pentylenetetrazole* ; Kindling, Neurologic*/drug effects; Animals ; Male ; Rats ; Drug Repositioning ; Rats, Wistar ; Oxidative Stress/drug effects ; Disease Models, Animal ; Antioxidants/pharmacology ; Antioxidants/therapeutic use ; Anticonvulsants/pharmacology ; Anticonvulsants/therapeutic use
    • Abstract:
      Epilepsy is a neurological disorder characterized by recurrent spontaneous seizures alongside other neurological comorbidities. Cognitive impairment is the most frequent comorbidity secondary to progressive neurologic changes in epilepsy. Sigma 1 receptors (σ1 receptors) are involved in the neuroprotection and pathophysiology of both conditions and targeting these receptors may have the potential to modulate both seizures and comorbidities. The current research demonstrated the effect of clemastine (10 mg/kg, P.O.), a non-selective σ1 receptor agonist, on pentylenetetrazol (PTZ) (35 mg/kg, i.p., every 48 h for 14 doses)-kindling rats by acting on σ1 receptors through its anti-inflammatory/antioxidant capacity. Clemastine and phenytoin (30 mg/kg, P.O.) or their combination were given once daily. Clemastine treatment showed a significant effect on neurochemical, behavioural, and histopathological analyses through modulation of σ1 receptors. It protected the kindling animals from seizures and attenuated their cognitive impairment in the Morris water maze test by reversing the PTZ hippocampal neuroinflammation/oxidative stress state through a significant increase in inositol-requiring enzyme 1 (IRE1), x-box binding protein 1 (XBP1), along with a reduction of total reactive oxygen species (TROS) and amyloid beta protein (Aβ). The involvement of σ1 receptors in the protective effects of clemastine was confirmed by their abrogation when utilizing NE-100, a selective σ1 receptor antagonist. In light of our findings, modulating σ1 receptors emerges as a compelling therapeutic strategy for epilepsy and its associated cognitive impairments. The significant neuroprotective effects observed with clemastine underscore the potential of σ1 receptor-targeted treatments to address both the primary symptoms and comorbidities of neurological disorders.
      Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest.
      (Copyright © 2024 Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Clemastine; Cognition impairment; IRE-1; Pentylenetetrazol; Sigma 1 receptor; XBP1
    • Accession Number:
      0 (Receptors, sigma)
      0 (Sigma-1 Receptor)
      0 (Neuroprotective Agents)
      WM5Z385K7T (Pentylenetetrazole)
      0 (Antioxidants)
      0 (Anticonvulsants)
    • Publication Date:
      Date Created: 20240731 Date Completed: 20240824 Latest Revision: 20240824
    • Publication Date:
      20240826
    • Accession Number:
      10.1016/j.ejphar.2024.176851
    • Accession Number:
      39084454