| 1 | J. Neurosci. Res. 2012 Jan 90: 288-306 |
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| PMID | 21932359 |
| Title | Chronic administration of the neurotrophic agent cerebrolysin ameliorates the behavioral and morphological changes induced by neonatal ventral hippocampus lesion in a rat model of schizophrenia. |
| Abstract | Neonatal ventral hippocampal lesion (nVHL) in rats has been widely used as a neurodevelopmental model to mimic schizophrenia-like behaviors. Recently, we reported that nVHLs result in dendritic retraction and spine loss in prefrontal cortex (PFC) pyramidal neurons and medium spiny neurons of the nucleus accumbens (NAcc). Cerebrolysin (CBL), a neurotrophic peptide mixture, has been reported to ameliorate the synaptic and dendritic pathology in models of aging and neurodevelopmental disorder such as Rett syndrome. This study sought to determine whether CBL was capable of reducing behavioral and neuronal alterations in nVHL rats. The behavioral analysis included locomotor activity induced by novel environment and amphetamine, social interaction, and sensoriomotor gating. The morphological evaluation included dendritic analysis by using the Golgi-Cox procedure and stereology to quantify the total cell number in PFC and NAcc. Behavioral data show a reduction in the hyperresponsiveness to novel environment- and amphetamine-induced locomotion, with an increase in the total time spent in social interactions and in prepulse inhibition in CBL-treated nVHL rats. In addition, neuropathological analysis of the limbic regions also showed amelioration of dendritic retraction and spine loss in CBL-treated nVHL rats. CBL treatment also ameliorated dendritic pathology and neuronal loss in the PFC and NAcc in nVHL rats. This study demonstrates that CBL promotes behavioral improvements and recovery of dendritic neuronal damage in postpubertal nVHL rats and suggests that CBL may have neurotrophic effects in this neurodevelopmental model of schizophrenia. These findings support the possibility that CBL has beneficial effects in the management of schizophrenia symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Int. J. Dev. Neurosci. 2013 Dec 31: 790-5 |
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| PMID | 24120877 |
| Title | Effect of prenatal stress on density of NMDA receptors in rat brain. |
| Abstract | N-methyl-D-aspartate (NMDA) receptors are important excitatory receptors which contribute to many brain functions. Altered NMDA receptor levels cause maldevelopment of corticostriatal and corticolimbic pathways, which is a neurobiological predisposing factor for development of epilepsy, schizophrenia and other idiopathic psychotic disorders. It was hypothesized that prenatal stress could play a role in pathophysiology of these disorders by affecting expression of the receptors through releasing corticosterone. Sixty-eight virgin female Wistar rats were selected and mated with male rats with the same genotype. Then, the pregnant rats were subjected to restraint or predator stress on 15th, 16th and 17th gestation days. Prenatal stress consisted of restraint or predator stresses of the dams under normal room conditions. After parturition, the pups were studied in terms of density of NMDA receptors in brain at different time points. Meanwhile, blood sample was obtained and corticosterone blood level (CBL) was measured. The pups were then compared with the pups born to unstressed dams. Stress induced significant rise in CBL and NMDA receptors in brain of the offspring. CBL was significantly higher among the stressed rats compared to the control ones; there was significant difference between the two stresses and between the two sexes. The male pups were affected more severely. Stressful events during gestation had important effects on NMDA receptors of the offspring. It can be concluded that stress-induced elevation of NMDA receptors and corticosterone might mediate altered susceptibility to epilepsy and decrease ability of learning and memory and other stress-induced neurologic disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Synapse 2014 Jan 68: 31-8 |
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| PMID | 24123373 |
| Title | Chronic cerebrolysin administration attenuates neuronal abnormalities in the basolateral amygdala induced by neonatal ventral hippocampus lesion in the rat. |
| Abstract | The neonatal ventral hippocampal lesion (nVHL) has emerged as a model of schizophrenia-related behavior in the rat. Our previous report demonstrated that cerebrolysin (CBL), a neuropeptide preparation which mimics the action of endogenous neurotrophic factors on brain protection and repair, promoted recovery of dendritic and neuronal damage of the prefrontal cortex and nucleus accumbens and behavioral improvements in postpubertal nVHL rats. We recently demonstrated that nVHL animals exhibit dendritic atrophy and spine loss in the basolateral amygdala (BLA). This study aimed to determine whether CBL treatment was capable of reducing BLA neuronal alterations observed in nVHL rats. The morphological evaluation included examination of dendrites using the Golgi-Cox procedure and stereology to quantify the total cell number in BLA. Golgi-Cox staining revealed that nVHL induced dendritic retraction and spine loss in BLA pyramidal neurons. Stereological analysis demonstrated nVHL also produced a reduction in cells in BLA. Interestingly, repeated CBL treatment ameliorated dendritic pathology and neuronal loss in the BLA of the nVHL rats. Our data show that CBL may foster recovery of BLA damage in postpubertal nVHL rats and suggests that the use of neurotrophic agents for the management of some schizophrenia-related symptoms may present an alternative therapeutic pathway in these disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | PLoS ONE 2016 -1 11: e0146797 |
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| PMID | 26799654 |
| Title | Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia. |
| Abstract | Many studies indicate a crucial role for the vitamin B12 and folate-dependent enzyme methionine synthase (MS) in brain development and function, but vitamin B12 status in the brain across the lifespan has not been previously investigated. Vitamin B12 (cobalamin, CBL) exists in multiple forms, including methylcobalamin (MeCBL) and adenosylcobalamin (AdoCBL), serving as cofactors for MS and methylmalonylCoA mutase, respectively. We measured levels of five CBL species in postmortem human frontal cortex of 43 control subjects, from 19 weeks of fetal development through 80 years of age, and 12 autistic and 9 schizophrenic subjects. Total CBL was significantly lower in older control subjects (> 60 yrs of age), primarily reflecting a >10-fold age-dependent decline in the level of MeCBL. Levels of inactive cyanocobalamin (CNCBL) were remarkably higher in fetal brain samples. In both autistic and schizophrenic subjects MeCBL and AdoCBL levels were more than 3-fold lower than age-matched controls. In autistic subjects lower MeCBL was associated with decreased MS activity and elevated levels of its substrate homocysteine (HCY). Low levels of the antioxidant glutathione (GSH) have been linked to both autism and schizophrenia, and both total CBL and MeCBL levels were decreased in glutamate-cysteine ligase modulatory subunit knockout (GCLM-KO) mice, which exhibit low GSH levels. Thus our findings reveal a previously unrecognized decrease in brain vitamin B12 status across the lifespan that may reflect an adaptation to increasing antioxidant demand, while accelerated deficits due to GSH deficiency may contribute to neurodevelopmental and neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | PLoS ONE 2016 -1 11: e0146797 |
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| PMID | 26799654 |
| Title | Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia. |
| Abstract | Many studies indicate a crucial role for the vitamin B12 and folate-dependent enzyme methionine synthase (MS) in brain development and function, but vitamin B12 status in the brain across the lifespan has not been previously investigated. Vitamin B12 (cobalamin, CBL) exists in multiple forms, including methylcobalamin (MeCBL) and adenosylcobalamin (AdoCBL), serving as cofactors for MS and methylmalonylCoA mutase, respectively. We measured levels of five CBL species in postmortem human frontal cortex of 43 control subjects, from 19 weeks of fetal development through 80 years of age, and 12 autistic and 9 schizophrenic subjects. Total CBL was significantly lower in older control subjects (> 60 yrs of age), primarily reflecting a >10-fold age-dependent decline in the level of MeCBL. Levels of inactive cyanocobalamin (CNCBL) were remarkably higher in fetal brain samples. In both autistic and schizophrenic subjects MeCBL and AdoCBL levels were more than 3-fold lower than age-matched controls. In autistic subjects lower MeCBL was associated with decreased MS activity and elevated levels of its substrate homocysteine (HCY). Low levels of the antioxidant glutathione (GSH) have been linked to both autism and schizophrenia, and both total CBL and MeCBL levels were decreased in glutamate-cysteine ligase modulatory subunit knockout (GCLM-KO) mice, which exhibit low GSH levels. Thus our findings reveal a previously unrecognized decrease in brain vitamin B12 status across the lifespan that may reflect an adaptation to increasing antioxidant demand, while accelerated deficits due to GSH deficiency may contribute to neurodevelopmental and neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |