Pharmacological impact on the expression of microglial and astroglial proteins involved in the regulation of epileptogenesis as a possible new strategy for epilepsy therapy
- Authors: Zubareva O.E.1, Roginskaya A.I.1, Kovalenko A.A.1
-
Affiliations:
- Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences
- Issue: Vol 18, No 4 (2023)
- Pages: 593-596
- Section: Conference proceedings
- URL: https://genescells.ru/2313-1829/article/view/623321
- DOI: https://doi.org/10.17816/gc623321
- ID: 623321
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Abstract
Epilepsy is a debilitating neurological disorder. While current antiepileptic medications can alleviate acute seizures, they do not typically prevent long-term brain damage caused by the chronic condition. Consequently, there is a pressing need for novel therapies that directly target epileptogenesis to address the comprehensive course and etiology of epilepsy.
For a considerable amount of time, research on the origin of epilepsy has chiefly concentrated on anomalies in the performance of neurons. As per typical theories, this is rooted in the unevenness between the performance of the excitatory (glutamate) and inhibitory neurotransmitter systems within the brain. Nevertheless, significant evidence has emerged in recent times that suggest the contribution of glial cells in the onset of epilepsy and the creation of neurological disorders following a seizure [1]. The astrocyte-produced excitatory amino acid transporter 2 (EAAT2) was found to regulate glutamatergic system activity, aiding the elimination of extracellular glutamate at central nervous system synapses. Astrocytes and microglia produce proteins that protect neurons from damage during epileptogenesis. In addition, astrocytes and microglia regulate neuroinflammation, which can worsen the development of epilepsy. Moreover, research demonstrated that astrocytes and microglia can have distinct functional states, with the A1 and M1 phenotypes generating mainly proinflammatory factors, while the A2 and M2 phenotypes produce anti-inflammatory factors. Drugs that stimulate polarization of glial cells from M1/A1 to M2/A2 phenotypes were proposed to be a successful strategy for treating inflammatory diseases, including epilepsies [2].
Numerous scientific findings indicate that peroxisome proliferator-activated receptor agonists (PPARs) exhibit similar properties [3]. PPARs (α, β/ and ) are nuclear transcription factors that are integral to the mechanisms of gut-nerve interactions, primarily regulating lipid and energy metabolism. However, PPAR agonists are capable of regulating inflammatory and oxidative signaling pathways involved in the development of various neuropsychiatric disorders, such as epilepsy. Furthermore, prior research described the neuroprotective qualities of certain PPAR agonists in a temporal lobe epilepsy (TLE) model.
In this study, the effects of pioglitazone, a PPARγ agonist, and Bifidobacterium longum, a probiotic that stimulates PPARγ expression in the brain [4], on astroglial and microglial mRNA protein production in brain structures that may impact epileptogenesis were investigated.
The study used the lithium-pilocarpine model of temporal lobe epilepsy in male Wistar rats. This model is highly regarded as an effective experimental approach for studying different stages of epileptogenesis from the earliest phases of the disease, prior to seizure manifestation, to the chronic phase accompanied by the development of spontaneous recurrent seizures [5].
During epileptogenesis in experimental animals, we observed an increase in the expression of proinflammatory proteins (Nrlp3, Il1b, and Tnfa) and markers of microglial and astroglial cell activation (Aif1 and Gfap) in the temporal cortex and hippocampus. This was demonstrated through the use of reverse transcription and real-time polymerase chain reaction during both the latent and chronic phases of the model. The development of neurodegenerative processes in the brain and formation of behavioral disorders, which are characteristic of the lithium-pilocarpine model, accompany these changes.
Pioglitazone administration, at a dosage of 7 mg/kg via intraperitoneal injection, was performed 75 minutes after induction of the TLE model. This was followed by a daily dose of 1 mg/kg for 7 consecutive days. Brain sampling for biochemical analysis was conducted after the seven-day treatment period. Findings indicated the upregulation of the interleukin-1 receptor antagonist gene, Il1rn, as well as expression of neuroprotective proteins S100a10 and Tgfb1.
Over a 30-day period, rats in the lithium-pilocarpine TLE model were orally administered a dose of 109 CFU/rat of Bifidobacterium longum. This resulted in an enhanced expression of the IL1rn gene in the temporal cortex, ventral hippocampus, and amygdala, as well as a reduction in the severity of neurodegenerative and behavioral disorders associated with the TLE model. The sample was taken 24 hours after the final administration.
The results suggest that therapy targeting the expression of astroglial and microglial proteins could be a promising approach for developing new and comprehensive treatments for epilepsy. Further research on the effects of PPARα and PPARβ/δ agonists on the expression of these genes is necessary, as it remains poorly understood.
Full Text
Epilepsy is a debilitating neurological disorder. While current antiepileptic medications can alleviate acute seizures, they do not typically prevent long-term brain damage caused by the chronic condition. Consequently, there is a pressing need for novel therapies that directly target epileptogenesis to address the comprehensive course and etiology of epilepsy.
For a considerable amount of time, research on the origin of epilepsy has chiefly concentrated on anomalies in the performance of neurons. As per typical theories, this is rooted in the unevenness between the performance of the excitatory (glutamate) and inhibitory neurotransmitter systems within the brain. Nevertheless, significant evidence has emerged in recent times that suggest the contribution of glial cells in the onset of epilepsy and the creation of neurological disorders following a seizure [1]. The astrocyte-produced excitatory amino acid transporter 2 (EAAT2) was found to regulate glutamatergic system activity, aiding the elimination of extracellular glutamate at central nervous system synapses. Astrocytes and microglia produce proteins that protect neurons from damage during epileptogenesis. In addition, astrocytes and microglia regulate neuroinflammation, which can worsen the development of epilepsy. Moreover, research demonstrated that astrocytes and microglia can have distinct functional states, with the A1 and M1 phenotypes generating mainly proinflammatory factors, while the A2 and M2 phenotypes produce anti-inflammatory factors. Drugs that stimulate polarization of glial cells from M1/A1 to M2/A2 phenotypes were proposed to be a successful strategy for treating inflammatory diseases, including epilepsies [2].
Numerous scientific findings indicate that peroxisome proliferator-activated receptor agonists (PPARs) exhibit similar properties [3]. PPARs (α, β/ and ) are nuclear transcription factors that are integral to the mechanisms of gut-nerve interactions, primarily regulating lipid and energy metabolism. However, PPAR agonists are capable of regulating inflammatory and oxidative signaling pathways involved in the development of various neuropsychiatric disorders, such as epilepsy. Furthermore, prior research described the neuroprotective qualities of certain PPAR agonists in a temporal lobe epilepsy (TLE) model.
In this study, the effects of pioglitazone, a PPARγ agonist, and Bifidobacterium longum, a probiotic that stimulates PPARγ expression in the brain [4], on astroglial and microglial mRNA protein production in brain structures that may impact epileptogenesis were investigated.
The study used the lithium-pilocarpine model of temporal lobe epilepsy in male Wistar rats. This model is highly regarded as an effective experimental approach for studying different stages of epileptogenesis from the earliest phases of the disease, prior to seizure manifestation, to the chronic phase accompanied by the development of spontaneous recurrent seizures [5].
During epileptogenesis in experimental animals, we observed an increase in the expression of proinflammatory proteins (Nrlp3, Il1b, and Tnfa) and markers of microglial and astroglial cell activation (Aif1 and Gfap) in the temporal cortex and hippocampus. This was demonstrated through the use of reverse transcription and real-time polymerase chain reaction during both the latent and chronic phases of the model. The development of neurodegenerative processes in the brain and formation of behavioral disorders, which are characteristic of the lithium-pilocarpine model, accompany these changes.
Pioglitazone administration, at a dosage of 7 mg/kg via intraperitoneal injection, was performed 75 minutes after induction of the TLE model. This was followed by a daily dose of 1 mg/kg for 7 consecutive days. Brain sampling for biochemical analysis was conducted after the seven-day treatment period. Findings indicated the upregulation of the interleukin-1 receptor antagonist gene, Il1rn, as well as expression of neuroprotective proteins S100a10 and Tgfb1.
Over a 30-day period, rats in the lithium-pilocarpine TLE model were orally administered a dose of 109 CFU/rat of Bifidobacterium longum. This resulted in an enhanced expression of the IL1rn gene in the temporal cortex, ventral hippocampus, and amygdala, as well as a reduction in the severity of neurodegenerative and behavioral disorders associated with the TLE model. The sample was taken 24 hours after the final administration.
The results suggest that therapy targeting the expression of astroglial and microglial proteins could be a promising approach for developing new and comprehensive treatments for epilepsy. Further research on the effects of PPARα and PPARβ/δ agonists on the expression of these genes is necessary, as it remains poorly understood.
ADDITIONAL INFORMATION
Funding sources. The study was supported by a grant from the Russian Science Foundation (project No. 23-25-00480).
About the authors
O. E. Zubareva
Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences
Author for correspondence.
Email: ZubarevaOE@mail.ru
Russian Federation, Saint Petersburg
A. I. Roginskaya
Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences
Email: ZubarevaOE@mail.ru
Russian Federation, Saint Petersburg
A. A. Kovalenko
Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences
Email: ZubarevaOE@mail.ru
Russian Federation, Saint Petersburg
References
- Patel DC, Tewari BP, Chaunsali L, Sontheimer H. Neuron–glia interactions in the pathophysiology of epilepsy. Nature Reviews Neuroscience. 2019;20:282–297. doi: 10.1038/s41583-019-0126-4
- Song GJ, Suk K. Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases. Frontiers in Aging Neuroscience. 2017;9:139. doi: 10.3389/fnagi.2017.00139
- Ji J, Xue TF, Guo XD, et al. Antagonizing peroxisome proliferator-activated receptor γ facilitates M1-to-M2 hift of microglia by enhancing autophagy via the LKB1-AMPK signaling pathway. Aging Cell. 2018;17(4):e12774. doi: 10.1111/acel.12774
- Zubareva OE, Dyomina AV, Kovalenko AA, et al. Beneficial Effects of Probiotic Bifidobacterium longum in a Lithium-Pilocarpine Model of Temporal Lobe Epilepsy in Rats. International Journal of Molecular Sciences. 2023;24(9):8451. doi: 10.3390/ijms24098451
- Dyomina AV, Zubareva OE, Smolensky IV, et al. Anakinra reduces epileptogenesis, provides neuroprotection, and attenuates behavioral impairments in rats in the lithium–pilocarpine model of epilepsy. Pharmaceuticals. 2023;13(11):340. doi: 10.3390/ph13110340
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