ABSTRACT
Introduction: Although pharmacotherapy is the most common treatment for epilepsy, proper seizure control is not achieved with current medications. This study evaluated the protective effects of the Hepatocyte Growth Factor (HGF) in a rat model of Temporal Lobe Epilepsy (TLE) and explored possible molecular mechanisms. Methods: A TLE rat model was determined using an intra-hippocampal kainic acid injection (4 µg). Intra-cerebrovascular injection of HGF (6 µg) was performed 30 min before kainic acid injection. Learning and memory impairment were investigated by behavioral tests. The Enzyme-Linked Immunosorbent (ELISA) was used to determine astrogliosis and DNA fragmentation. Changes in neuronal density and mossy fiber sprouting were evaluated by Nissl and Timm staining, respectively. Results: Behavioral assessments indicated that kainate-treated rats presented spontaneous seizures. Moreover, their alternation percentage scores in the Y-Maze test were lower (P<0.001). Likewise, the passive avoidance test confirmed learning disability in Kainate-treated rats (P<0.001). HGF administration reduced the number of spontaneous seizures, alternation percentage score (P<0.001), and cognitive disturbances (P<0.001). The histopathological results also showed that a protected HGF administration contributed to the reduction of neuronal loss in the CA3 subregion of the hippocampus and inhibited the formation of aberrant Mossy Fiber Sprouting (MFS) (P<0.01). Furthermore, the ELISA data indicated a significant decrease in GFAP (P<0.01) and DNA fragmentation (P<0.05) following HGF administration. Conclusion: Our findings demonstrated the validity of HGF in protection against the progression of the kainate-induced TLE in rats. This measure improved learning, cognitive disturbances and inhibited apoptosis and astrogliosis. Highlights: Temporal lobe epilepsy results in apoptosis of neuronal cells;Hepatocyte growth factor attenuates the severity of status epilepticus in kainic acid-induced model;Hepatocyte growth factor attenuates apoptosis of neuronal cells in kainic acid-induced model of temporal lobe epilepsy. Plain Language Summary: Epilepsy is known as a disorder of the CNS which is caused by an imbalance in the electrical activity of neurons that in turn results in derangement in cognitive or causing debilitating seizures. Hepatocyte growth factor is one of neurotrophins secreted from mesenchymal and epithelial cells that regulate the growth, survival and functional changes of cells through signaling pathways such as the tyrosine kinase pathway after binding to its specific receptor. In this study, we tried to find out the effect of hepatocyte growth factor on attenuation of the severity of status epilepticus in kainic acid-induced model of temporal lobe epilepsy. Our results show that hepatocyte growth factor is able to protect against progression of the kainate-induced temporal lobe epilepsy in rats by improvement of learning, cognitive disturbances and inhibiting of apoptosis and astrogliosis.
ABSTRACT
INTRODUCTION: Cognitive dysfunction is the most common problem of patients with Alzheimer Disease (AD). The pathological mechanism of cognitive impairment in AD may contribute to neuronal loss, synaptic dysfunction, and alteration in neurotransmitters receptors. Mitochondrial synapses dysfunction due to the accumulation of Amyloid Beta (Aß) is one of the earliest pathological features of AD. The flavone apigenin has been reported to play some protective roles in AD through the anti-oxidative and anti-inflammatory properties. This study aimed at investigating the effects of apigenin on spatial working memory and neural protection by restoring mitochondrial dysfunction and inhibition of caspase 9. METHODS: Intracerebroventricular (ICV) microinjection of Aß 25-35 was used for AD modeling. Working memory was assessed 21 days later using the Y maze test. Neuronal loss was detected in the hilar area of the hippocampus using Nissl and Fluoro-jade B staining, whereas immunohistochemistry was used to illustrate cytochrome c positive cells and caspase 9. RESULTS: The results revealed that apigenin significantly ameliorated spatial working memory. It also significantly reduced the number of degenerative neurons in the hilus area. Apigenin almost completely blocked the release of cytochrome c and caspase 9 in hilus. CONCLUSION: Apigenin may improve the spatial working memory deficits and neuronal degeneration through the amelioration of the mitochondrial dysfunction.
ABSTRACT
Parkinson's disease (PD) is a prevalent movement disorder in the elderly. PD is hallmarked with progressive deterioration of mesencephalic dopaminergic neurons and development of debilitating motor and non-motor clinical symptoms. Klotho protein is the product of an aging-suppressor gene that its overexpression could protect neurons against oxidative injury. This study was undertaken to explore whether exogenous klotho could alleviate injury of nigrostriatal dopaminergic pathway in 6-hydroxydopamine (6-OHDA) rat model of PD. Intrastriatal 6-OHDA-lesioned rats were pretreated with klotho at a dose of 10µg/rat. Results showed that klotho mitigates apomorphine-induced rotational behavior and reduces the latency to initiate and the total time in the narrow beam test. In addition, beneficial effect of klotho was attenuated following i.c.v. microinjection of protein kinase A (PKA) inhibitor H-89 and Ca(2+)/calmodulin-dependent protein kinase II (CamKII) inhibitor KN-62. Additionally, klotho significantly lowered striatal levels of malondialdehyde (MDA), reactive oxygen species (ROS), glial fibrillary acid protein (GFAP), α synuclein, phospho-cAMP-response element binding protein (pCREB), and DNA fragmentation. Furthermore, klotho was capable to prevent degeneration of tyrosine hydroxylase (TH)-positive neurons within substantia nigra pars compacta (SNC). Collectively, these findings denote neuroprotective potential of exogenous klotho in 6-OHDA rat model of PD through alleviation of astrogliosis, apoptosis, and oxidative stress. It was also obtained that part of its protective effect is dependent on PKA/CaMKII/CREB signaling cascade.
