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Pentylenetetrazole-Induced Kindling Mouse Model
Published on: June 12, 2018
Prefrontal TRPM8 Receptor Modulates Epileptic Seizures via PKA/CREB Signaling Pathway in Mice
Jia-Zhan Huang1,2, Gui-Feng Lu3, Yi-Han Jiang2
1Department of Stomatology, Shantou University Medical College, Shantou, China.
Aim:
Epilepsy is a common neurological disorder accompanied by mental and cognitive impairment, which affects approximately 50 million people worldwide. Recent studies revealed that transient receptor potential melastatin 8 (TRPM8) receptors exerted a significant effect in PTZ-induced acute seizure model. However, the exact function and mechanism of prefrontal TRPM8 receptor in seizures remain unclear. This study aimed to investigate the upstream and downstream signaling pathways of TRPM8 receptors and how they jointly regulate the occurrence and development of seizures.
Methods:
Pentylenetetrazol (PTZ) was used to establish an acute mouse seizure model, and the seizure behavior of TRPM8 channel block mice and normal mice was observed and analyzed. Specific blocking of TRPM8 channels in specific brain regions was performed by stereotactic injection into the brain. The expression of TRPM8 downstream signaling molecules in the prefrontal cortex (PFC) and the apoptosis of neuronal cells were analyzed after PTZ-induced acute seizures.
Results:
TRPM8 receptors were upregulated in the PFC of mice with seizures. Inhibition or knockdown of TRPM8 in the PFC can effectively prolong the latency and reduce the level of seizures in mouse models induced by PTZ. Meanwhile, prefrontal TRPM8, Phosphorylated PKA (p-PKA) and Phosphorylated CREB (p-CREB) levels were upregulated during seizures. In the PTZ-induced acute seizure cell model, the expression of TRPM8, p-CREB, and p-PKA was also increased, but this effect was reversed by the TRPM8 inhibitor AMTB. PKA agonists significantly offset the effects of TRPM8 inhibitors in prolonging latency and reducing seizure levels. Finally, TUNEL staining showed that the apoptosis rate of prefrontal neurons in seizure mice decreased after TRPM8 inhibition and knockdown, while PKA activation could counteract the AMTB-induced decrease in neuronal apoptosis.
Conclusion:
Prefrontal TRPM8 receptor plays a vital role in PTZ-induced acute seizures through the PKA/CREB pathway, which provides a potential target for the treatment of seizures.
Insights
Blocking prefrontal transient receptor potential melastatin 8 (TRPM8) receptors reduces seizure severity and neuronal apoptosis in a mouse model. This pathway involves the PKA/CREB signaling cascade, offering a potential therapeutic target for epilepsy treatment.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Epilepsy affects 50 million worldwide, often with cognitive impairments.
- Transient receptor potential melastatin 8 (TRPM8) receptors are implicated in acute seizure models.
- The precise role of prefrontal TRPM8 in seizure mechanisms remains largely unknown.
Purpose of the Study:
- Investigate the upstream and downstream signaling pathways of prefrontal TRPM8 receptors.
- Determine how TRPM8 jointly regulates seizure occurrence and progression.
- Explore TRPM8 as a potential therapeutic target for seizure disorders.
Main Methods:
- Established an acute mouse seizure model using pentylenetetrazol (PTZ).
- Utilized stereotactic injections for region-specific TRPM8 channel blockade in the prefrontal cortex (PFC).
- Analyzed seizure behavior, TRPM8 downstream signaling molecules (p-PKA, p-CREB), and neuronal apoptosis (TUNEL staining) post-PTZ induction.
Main Results:
- TRPM8 receptors and downstream p-PKA/p-CREB levels were upregulated in the PFC during PTZ-induced seizures.
- Inhibiting or knocking down TRPM8 in the PFC prolonged seizure latency and reduced seizure severity.
- TRPM8 inhibition decreased prefrontal neuronal apoptosis, an effect counteracted by PKA activation.
Conclusions:
- Prefrontal TRPM8 receptors are critical in PTZ-induced acute seizures.
- The PKA/CREB pathway is a key downstream mediator of TRPM8's role in seizures.
- Targeting prefrontal TRPM8 offers a promising therapeutic strategy for seizure management.
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