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Kainic acid (KA) is a most useful tool for the study of excitatory neurotoxicity. Local or systemic administration of KA in rodents leads to a pattern of repetitive limbic seizures and status epilepticus, accompanied by hippocampal degeneration. Insulin-like Growth Factor-I (IGF-I) is an important growth factor, which has been used as a therapeutic agent in a number of models of neurodegenerative diseases such as ischemia or trauma of the cortex or the spinal cord.In the present study, kainic acid (0.4ιg/0.4ιl) or kanic acid together with IGF-I (4ιg/0.4ιl) was stereotactically injected into the CA3 hippocampal area (AP: 1.8 mm, ML: 1.6 mm, DV: 2.4 mm) of male mice. Fifteen days following intrahippocampal administration of KA extended degeneration of the hippocampus was observed ipsilaterally to the injection site as revealed following cresyl violet staining. Hippocampal degeneration was also observed in the CA3 and CA4 hippocampal areas of the contralateral hemisphere. Heat-shock prote ...
Kainic acid (KA) is a most useful tool for the study of excitatory neurotoxicity. Local or systemic administration of KA in rodents leads to a pattern of repetitive limbic seizures and status epilepticus, accompanied by hippocampal degeneration. Insulin-like Growth Factor-I (IGF-I) is an important growth factor, which has been used as a therapeutic agent in a number of models of neurodegenerative diseases such as ischemia or trauma of the cortex or the spinal cord.In the present study, kainic acid (0.4ιg/0.4ιl) or kanic acid together with IGF-I (4ιg/0.4ιl) was stereotactically injected into the CA3 hippocampal area (AP: 1.8 mm, ML: 1.6 mm, DV: 2.4 mm) of male mice. Fifteen days following intrahippocampal administration of KA extended degeneration of the hippocampus was observed ipsilaterally to the injection site as revealed following cresyl violet staining. Hippocampal degeneration was also observed in the CA3 and CA4 hippocampal areas of the contralateral hemisphere. Heat-shock protein 70 (Hsp70) immunopositive cells were also observed in the ipsilateral CA1 and cortex, and in the CA3 hippocampal area of the contralateral hemisphere following KA injection. Furthermore, KA injection resulted in intense astrogliosis -as assessed by GFAP immunopositive cells- ipsilaterally to the injection site. In addition, cell death -as detected by FluoroJade B- staining was observed mainly in the CA3 and CA4 areas of the ipsilateral hippocampus. When IGF-I was administered together with KA there was a smaller degree of cell loss, reduced FluoroJade B staining, decreased reactive gliosis and fewer Hsp70 positive cells. In studies evaluating possible neuroprotective therapeutic agents, behavioral endpoints should always be examined. To assess the behavioural effects of KA or KA together with IGF-I administration we measured spatial learning and memory using the Morris water maze. Two maze diameters (85 and 140 cm) were used under identical training and testing conditions. Mice injected with either KA or KA together with IGF-I performed satisfactory in the small pool, a task which can be solved using only egocentric strategies. In the 140-cm-diameter setting (requiring allocentric strategies) KA injected mice had learning and memory impairments compared to animals injected with KA and IGF-I or control animals.Neuro-transplantation has been proposed in recent years as a potential treatment for neurodegenerative disorders. Neural Stem Cell (NSC) grafting represents a potential and innovative strategy for the treatment of many central nervous system disorders. After being grafted, NSCs have been shown to migrate to the lesioned regions of the brain and differentiate into the necessary type of cells needed to promote recovery.We transplanted NSCs (genetically modified with the IGF-I gene or not) expressing green fluorescent protein into the lesioned hippocampus, four days after an intrahippocampal administration of KA. We assessed the survival and migration of NSCs following KA administration at 8, 30 and 60 days. NSC differentiation was determined by immunohistochemistry for immature or mature neuronal (Nestin and NeuN), respectively as well as astroglial (GFAP) cell markers. The presence of IGF-I immunopositive NSCs was also investigated. Analysis of brains 8, 30 days after intrahippocampal transplantation of NSCs revealed only limited migration into the host brains. However, at 60 days after transplantation of NSCs, widespread distribution of cells was observed. Interestingly, some of the NSCs had migrated into the site of the KA-induced lesion. Subsets of grafted cells expressed neuronal (nestin+ and NeuN+), or in some cells astroglial (GFAP+) cell markers. Interestingly the morphology of the GFAP+/GFP cells was indicative of a radial glia phenotype. In addition, IGF-I/GFP double positive cells were detected. We also determined the effects of KA or KA with NSCs administration on spatial learning and memory using the Morris water maze at 60 days: KA injected mice had memory impairments compared to animals injected with KA and NSCs or control animals in the 140-cm-diameter setting (requiring allocentric strategies).These results suggest that IGF-I has neuroprotective properties, decreasing both neuronal death as well as astroglial reaction. Based on the above, we can conclude that IGF-I is an important neuroprotective agent which could possibly be used therapeutically in the future, and that NSCs can engraft successfully into KA-lesioned adult brain, where they can survive and disseminate into the lesion area and differentiate primarily into neuronal cells to replace lost neurons.
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