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Can endoplasmic reticulum stress observed in the PTZ-kindling model seizures be prevented with TUDCA and 4-PBA?

Doğanyiğit Z, Okan A, Akyüz E, Yılmaz S, Ateş Ş, Taheri S, et al.

Eur J Pharmacol, 2023 Oct 16;960:176072.
PMID: 37852571 DOI: 10.1016/j.ejphar.2023.176072

Epilepsy is a chronic neurological disease with recurrent seizures. Increasing evidence suggests that endoplasmic reticulum (ER) stress may play a role in the pathogenesis of epilepsy. We aimed to investigate the effects of Tauroursodeoxycholic acid (TUDCA) and 4-phenyl-butyric acid (4-PBA), which are known to suppress ER stress, on developed seizures in terms of markers of ER stress, oxidative stress, and apoptosis. The pentylenetetrazole (PTZ) kindling model was induced in Wistar albino rats (n = 48) by administering 35 mg/kg PTZ intraperitoneally (I.P.) every other day for 1 month. TUDCA and 4-PBA were administered via I.P. at a dose of 500 mg/kg dose. ER stress, apoptosis, and oxidative stress were determined in the hippocampus tissues of animals in all groups. Immunohistochemistry, qRT-PCR, ELISA, and Western Blot analyzes were performed to determine the efficacy of treatments. Expressions of ATF4, ATF6, p-JNK1/2, Cleaved-Kaspase3, and Caspase12 significantly increased in PTZ-kindled seizures compared to the control group. Increased NOX2 and MDA activity in the seizures were measured. In addition, stereology analyzes showed an increased neuronal loss in the PTZ-kindled group. qRT-PCR examination showed relative mRNA levels of CHOP. Accordingly, TUDCA and 4-PBA treatment suppressed the expressions of ATF4, ATF6, Cleaved-Caspase3, Kaspase12, NOX2, MDA, and CHOP in TUDCA + PTZ and 4-PBA + PTZ groups. ER stress-induced oxidative stress and apoptosis by reducing neuronal loss and degeneration were also preserved in these groups. Our data show molecularly that TUDCA and 4-PBA treatment can suppress the ER stress process in epileptic seizures.
Synaptic Function and Dysfunction: New Frontiers in CNS Disorders

Aslan FS, Akdag MB, Doganyigit Z, Okan A, Shaikh MF, Akyuz E

J Neurosci Res, 2025 Apr;103(4):e70033.
PMID: 40172089 DOI: 10.1002/jnr.70033

Central nervous system (CNS) disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and migraines, rank among the most prevalent and concerning conditions worldwide. Despite ongoing research, the pathophysiology of these disorders remains incompletely understood, primarily due to their complex etiology. Current pharmacological treatments mainly focus on alleviating symptoms rather than addressing the underlying causes of these diseases. CNS disorders are marked by impairments in neurocognitive and neuromuscular functions, and cognitive processes like learning and memory. This deterioration not only impacts the quality of life of affected individuals but also places a significant burden on their families. Neuroplasticity is a key property of the nervous system that enables brain repair and functional recovery. However, in CNS disorders, neuroplasticity is often compromised. Neuroplasticity, which is regulated by gene expression, is also modulated by environmental factors and epigenetic mechanisms, thereby reshaping neuronal networks in response to various biological and environmental stimuli and brain function. Importantly, neuroplasticity plays a critical role in repairing the brain, especially in the context of neurodegenerative diseases, where damaged neurons can reorganize and re-establish lost functions. Targeting neuroplasticity mechanisms holds significant potential for developing therapeutic interventions to improve treatment outcomes and prevent CNS disorders. A deeper understanding of neuroplasticity in neurological diseases could open new avenues for enhancing patient quality of life. This review aims to provide a comprehensive overview of synaptic function and the neuroplasticity mechanisms that are disrupted in neurological disorders.
Fulltext Traumatic brain injury-induced peripheral damage: The dynamics of the inflammatory and autophagy pathway from acute to chronic stages

Doğanyiğit Z, Taheri S, Okan A, Yılmaz Z, Üner AK, Akyüz E, et al.

Folia Neuropathol, 2024 Aug 21.
PMID: 39165216 DOI: 10.5114/fn.2024.140788

INTRODUCTION: Traumatic brain injury (TBI) is one of the major causes of death and disability worldwide, and brings a huge burden on the quality of life of patients with TBI and the country's healthcare system. Peripheral organs, especially the kidney, and liver, may be affected by the onset of molecular responses following brain tissue damage. While secondary injury responses post TBI has been well studied in the brain, the effect/consequences of these responses in the peripheral organs have not yet been fully elucidated. Thus, our study aimed to investigate the immunoreactivity of these responses, particularly via proinflammatory cytokines and autophagy markers in the kidney and liver post-acute and chronic TBI.
MATERIAL AND METHODS: Mild TBI (mTBI) and repetitive mTBI (r-mTBI) were induced in male and female 2-month-old Balb/c mice via the Marmarou weight-drop model. Liver and kidney tissues were sampled at 24 hours (acute) and 30 days (chronic) post TBI and subjected to histopathological and immunoreactivity analysis.
RESULTS: Interleukin (IL)-6 levels were significantly increased in the male liver and kidney tissues in both TBI groups compared to the control group but were seen to be decreased in the female r-mTBI chronic liver and r-mTBI acute kidney. Tumor necrosis factor a (TNF-a) levels were found to increase only in the female r-mTBI chronic kidney tissue and mTBI chronic liver tissue. IL-1b levels were increased in the male and female r-mTBI liver tissues but decreased in the female mTBI kidney tissue. Inducible nitric oxide synthase (iNOS) levels were found to be significantly increased in the female mTBI acute and r-mTBI chronic kidney tissue and mTBI liver tissue, but decreased in the r-mTBI acute kidney and r-mTBI liver tissues. Beclin-1 levels were increased in male mTBI chronic and r-mTBI acute liver tissue but decreased in the r-mTBI chronic group. LC3A/B and P62/SQSTM1 levels were significantly increased in the female mTBI chronic and male r-mTBI chronic liver tissues but decreased in the male r-mTBI and female r-mTBI acute kidney tissues. Significant histopathological changes were also observed in the liver and kidney tissue which were dependent on the TBI severity, gender, and time post TBI.
CONCLUSIONS: The results showed that TBI may elicit peripheral molecular responses, particularly in terms of alteration in the levels of inflammatory cytokines and autophagy markers, which were gender- and time-dependent. This suggests that TBI may have a significant role in the cellular damage of the kidney and liver in both the acute and chronic phases post TBI, thus ensuring that the effects of TBI may not be confined to the brain.

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