scholarly journals DL-3-n-butylphthalide promotes hippocampal neurogenesis and reduces mossy fiber sprouting in chronic temporal lobe epilepsy rats

BMC Neurology ◽  
2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Shanshan Zhao ◽  
Fangxi Liu ◽  
Wei Shi ◽  
Jialu Wang ◽  
Zhike Zhou ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Function ◽  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Mossy Fiber ◽  
Hippocampal Neurogenesis ◽  
Immunofluorescent Staining ◽  
Mossy Fiber Sprouting ◽  
Spontaneous Seizures ◽  
Newborn Neurons

Abstract Background A decrease in hippocampal neurogenesis is considered an important cause of cognitive impairment, while changes in mossy fiber sprouting are closely related to development of spontaneous recurrent seizures in chronic temporal lobe epilepsy (TLE). Racemic l-3-n-butylphthalide (DL-NBP) can alleviate cognitive impairment in ischemic stroke and Alzheimer’s disease by promoting neurogenesis. DL-NBP treatment can also improve cognitive function and reduce seizure incidence in chronic epileptic mice. However, the mechanisms of action of DL-NBP remain unclear. The aim of the present study was to examine the effects of DL-NBP on mossy fiber sprouting, hippocampal neurogenesis, spontaneous epileptic seizures, and cognitive functioning in the chronic phase of TLE. Methods Nissl staining was used to evaluate hippocampal injury, while immunofluorescent staining was used to analyze hippocampal neurogenesis. The duration of spontaneous seizures was measured by electroencephalography. The Morris water maze was used to evaluate cognitive function. Timm staining was used to assess mossy fiber sprouting. Results TLE animals showed reduced proliferation of newborn neurons, cognitive dysfunction, and spontaneous seizures. Treatment with DL-NBP after TLE increased the proliferation and survival of newborn neurons in the dentate gyrus, reversed the neural loss in the hippocampus, alleviated cognitive impairments, and decreased mossy fiber sprouting and long-term spontaneous seizure activity. Conclusions We provided pathophysiological and morphological evidence that DL-NBP might be a useful therapeutic for the treatment of TLE.

Spontaneous Excitatory Currents and κ-Opioid Receptor Inhibition in Dentate Gyrus Are Increased in the Rat Pilocarpine Model of Temporal Lobe Epilepsy

1997 ◽  
Vol 78 (4) ◽  
pp. 1860-1868 ◽  
Author(s):  
Michele L. Simmons ◽  
Gregory W. Terman ◽  
Charles Chavkin
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Dentate Gyrus ◽  
Opioid Receptor ◽  
Temporal Lobe ◽  
Mossy Fiber ◽  
Perforant Path ◽  
Mossy Fiber Sprouting ◽  
Receptor Inhibition ◽  
Excitatory Activity ◽  
Pilocarpine Model

Simmons, Michele L., Gregory W. Terman, and Charles Chavkin. Spontaneous excitatory currents and κ-opioid receptor inhibition in dentate gyrus are increased in the rat pilocarpine model of temporal lobe epilepsy. J. Neurophysiol. 78: 1860–1868, 1997. Temporal lobe epilepsy is associated with a characteristic pattern of synaptic reorganization in the hippocampal formation, consisting of neuronal loss and aberrant growth of mossy fiber collaterals into the dentate gyrus inner molecular layer. We have used the rat pilocarpine model of temporal lobe epilepsy to study the functional consequences of mossy fiber sprouting on excitatory activity and κ-opioid receptor-mediated inhibition. Using the whole cell voltage-clamp technique, we found that abnormal excitatory activity was evident in granule cells of the dentate gyrus from pilocarpine-treated rats. The frequency of spontaneous excitatory postsynaptic currents (EPSCs) was increased greatly in cells from tissue in which significant mossy fiber sprouting had developed. In the presence of bicuculline, giant spontaneous EPSCs, with large amplitudes and long durations, were seen only in association with mossy fiber sprouting. Giant EPSCs also could be evoked by low-intensity stimulation of the perforant path. Mossy fibers release not only excitatory amino acids, but also opioid peptides. κ-Opioid receptor-mediated inhibition in normal Sprague-Dawley rats was seen only in hippocampal sections from the ventral pole. In pilocarpine-treated rats, however, kappa receptor-mediated effects were seen in both ventral and more dorsal sections. Thus in this model of temporal lobe epilepsy, several types of abnormal excitatory activity were observed, thereby supporting the idea that mossy fiber sprouting leads to recurrent excitatory connections. At the same time, inhibition of excitatory activity by κ-opioid receptors was increased, perhaps representing an endogenous anticonvulsant mechanism.

Mossy fiber sprouting and pyramidal cell dispersion in the hippocampal CA2 region in a mouse model of temporal lobe epilepsy

Hippocampus ◽  
2015 ◽  
Vol 26 (5) ◽  
pp. 577-588 ◽  
Author(s):  
Ute Häussler ◽  
Katrin Rinas ◽  
Antje Kilias ◽  
Ulrich Egert ◽  
Carola A. Haas
Keyword(s):  
Mouse Model ◽  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Pyramidal Cell ◽  
Mossy Fiber ◽  
Mossy Fiber Sprouting ◽  
Cell Dispersion

scholarly journals High-dose rapamycin blocks mossy fiber sprouting but not seizures in a mouse model of temporal lobe epilepsy

Epilepsia ◽  
2013 ◽  
Vol 54 (9) ◽  
pp. 1535-1541 ◽  
Author(s):  
Kathleen Heng ◽  
Megan M. Haney ◽  
Paul S. Buckmaster
Keyword(s):  
Mouse Model ◽  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Mossy Fiber ◽  
High Dose ◽  
Mossy Fiber Sprouting

scholarly journals Association Between the Density of Mossy Fiber Sprouting and Seizure Frequency in Experimental and Human Temporal Lobe Epilepsy

Epilepsia ◽  
2000 ◽  
Vol 41 (s6) ◽  
pp. S24-S29 ◽  
Author(s):  
Asla Pitkanen ◽  
Jari Nissinen ◽  
Katarzyna Lukasiuk ◽  
Leena Jutila ◽  
Leo Paljarvi ◽  
...  
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Seizure Frequency ◽  
Mossy Fiber ◽  
Mossy Fiber Sprouting ◽  
Human Temporal Lobe

scholarly journals Reassessment of the Effects of Cycloheximide on Mossy Fiber Sprouting and Epileptogenesis in the Pilocarpine Model of Temporal Lobe Epilepsy

2002 ◽  
Vol 88 (4) ◽  
pp. 2075-2087 ◽  
Author(s):  
Philip A. Williams ◽  
Jean-Pierre Wuarin ◽  
Ping Dou ◽  
Damien J. Ferraro ◽  
F. Edward Dudek
Keyword(s):  
Status Epilepticus ◽  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Granule Cell Layer ◽  
Mossy Fiber Sprouting ◽  
Neuron Loss ◽  
Timm Staining ◽  
Pre Treatment

A feature of animal models of temporal lobe epilepsy and the human disorder is hippocampal sclerosis and Timm stain in the inner molecular layer (IML) of the dentate gyrus, which represents synaptic reorganization and may be important in epileptogenesis. We reassessed the hypothesis that pre-treatment with cycloheximide (CHX) prevents Timm staining in the IML following pilocarpine (PILO)-induced status epilepticus (a multifocal model of temporal lobe epilepsy), but allows epileptogenesis (i.e., chronic spontaneous seizures) after a latent period. Hippocampal slices from PILO-treated rats without Timm stain in the IML after CHX treatment were hypothesized to lack the electrophysiological abnormalities suggestive of recurrent excitation. The primary experimental groups were as follows: 1) CHX (1 mg/kg) 30–45 min prior to administration of PILO (320 mg/kg ip, 2) only PILO, and 3) only saline (0.5 ml, IP). The CHX pre-treatment significantly decreased the number of rats that responded to PILO with status epilepticus compared to rats that received only PILO. Pre-treatment with CHX did not significantly alter the spontaneous motor seizure rate post-treatment compared to treatment with PILO alone in those animals from each group that developed status epilepticus during PILO treatment. Timm stain in the IML was not significantly different between the PILO- and PILO+CHX-treated rats. Using quantitative methods, CHX did not prevent hilar, CA1, or CA3 neuronal loss compared to the PILO-treated rats. Extracellular responses to hilar stimulation in 30 μM bicuculline and 6 mM [K+]o demonstrated all-or-none bursting in both the CHX+PILO- and PILO-treated rats but not in control rats. Whole cell recordings from granule cells, using glutamate flash photolysis to activate other granule cells, showed that both the CHX+PILO- and PILO-treated rats had excitatory synaptic interactions in the granule cell layer, which were not found after saline treatment. Some rats responded to PILO (with or without CHX pre-treatment) with only one or a few seizures at treatment, and some of these animals ( n = 4) demonstrated spontaneous motor seizures within 2 mo after treatment. Timm staining and neuron loss in this group were not clearly different from saline-treated rats. These results suggest that in the PILO model, pre-treatment with CHX does not affect mossy fiber sprouting in the IML of epileptic rats and does not prevent the formation of recurrent excitatory circuits. However, the develoment of spontaneous motor seizures, in a small number of rats, could occur without detectable hippocampal neuron loss or mossy fiber sprouting, as assessed by the Timm stain method.

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