R E Gonzalez-Castaneda

Beneficial effects of α-lipoic acid plus vitamin E on neurological deficit, reactive gliosis and neuronal remodeling in the penumbra of the ischemic rat brain

During cerebral ischemia-reperfusion, the enhanced production of oxygen-derived free radicals contributes to neuronal death. The antioxidants alpha-lipoic acid and vitamin E have shown synergistic effects against lipid peroxidation by oxidant radicals in several pathological conditions. A thromboembolic stroke model in rats was used to analyze the effects of this mixture under two oral treatments: intensive and prophylactic. Neurological functions, glial reactivity and neuronal remodeling were assessed after experimental infarction. Neurological recovery was only found in the prophylactic group, and both antioxidant schemes produced down-regulation of astrocytic and microglial reactivity, as well as higher neuronal remodeling in the penumbra area, as compared with controls. The beneficial effects of this antioxidant mixture suggest that it may be valuable for the treatment of cerebral ischemia in humans.

An alpha-lipoic acid–vitamin E mixture reduces post-embolism lipid peroxidation, cerebral infarction, and neurological deficit in rats

Oxidative stress increases delayed neuronal death in the brain following ischemia. As a consequence, many attempts to reduce the damage resulting from cerebral ischemia under more highly oxidized conditions have focused on treatments aimed at maintaining the redox equilibrium of the local environment. This study demonstrates the synergistic effects of combining treatments with alpha-lipoic acid (LA) and vitamin E (VE) as an efficient measure to reduce the damage caused by cerebral ischemia. Two oral therapeutic protocols were examined: intensive treatment (100 mg/kg LA and 140 mg/kg VE for 7 days after ischemia) and prophylactic treatment (20 mg/kg LA and 50 mg/kg VE from 30 days before infarction up to the day of sacrifice). The prophylactic treatment reduced serum lipid peroxidation, and diminished brain infarct volume by approximately 50%. Furthermore, prophylactically treated rats showed a reduction in post-ischemia neurological scores. No significant differences were found in the intensively treated group. Our data indicate that pre-ischemia administration of the LA-VE antioxidant mixture reduced the volume of brain damaged and the functional consequences of embolic infarction. These findings suggest that prophylaxis with an LA-VE mixture may be valuable in reducing cerebral damage levels in patients with a high risk of stroke.

Prednisone induces cognitive dysfunction, neuronal degeneration, and reactive gliosis in rats.

Background High glucocorticoid serum levels and prednisone (PDN) therapy have been associated with depression, posttraumatic stress disorder, and some types of cognitive dysfunction in humans. Objective The aim of this study was to assess whether chronic (90 days) PDN administration produces disturbance in learning and memory retention associated with neuronal degeneration and cerebral glial changes. Methods Male Wistar rats were studied. Controls received 0.1 ml distilled water vehicle orally. The PDN group was treated orally with 5 mg/kg/d PDN, which is equivalent to moderate doses used in clinical settings. Learning and memory retention were assessed with the Morris water maze. The index of degenerated neurons as well as the number and cytoplasmic transformation of astrocytes and microglia cells were evaluated in the prefrontal cortex and the CA1 hippocampus. Results PDN-treated rats showed a significant delay of 20% in learning and memory retention as compared with controls. In addition, in the PDN group, the neuronal degeneration index was two times higher in the prefrontal cortex, and approximately 10 times higher in the CA1 hippocampus, than in control animals. The number and cytoplasmic transformation of astrocytes were also significantly higher in the PDN group than in control animals. In the PDN-treated group, isolectin-B4-labeled microglia cells were higher in the prefrontal cortex but not in the hippocampus. Conclusion These results suggest that chronic exposure to PDN produces learning and memory impairment, reduces neural viability, and increases glial reactivity in cerebral regions with these cognitive functions.

Role of Fibroblast Growth Factor Receptors in Astrocytic Stem Cells

There are two well-defined neurogenic regions in the adult brain, the subventricular zone (SVZ) lining the lateral wall of the lateral ventricles and, the subgranular zone (SGZ) in the dentate gyrus at the hippocampus. Within these neurogenic regions, there are neural stem cells with astrocytic characteristics, which actively respond to the basic fibroblast growth factor (bFGF, FGF2 or FGF-β) by increasing their proliferation, survival and differentiation, both in vivo and in vitro. FGF2 binds to fibroblast growth factor receptors 1 to 4 (FGFR1, FGFR2, FGFR3, FGFR4). Interestingly, these receptors are differentially expressed in neurogenic progenitors. During development, FGFR-1 and FGFR-2 drive oligodendrocytes and motor neuron specification. In particular, FGFR-1 determines oligodendroglial and neuronal cell fate, whereas FGFR-2 is related to oligodendrocyte specification. In the adult SVZ, FGF-2 promotes oligodendrogliogenesis and myelination. FGF-2 deficient mice show a reduction in the number of new neurons in the SGZ, which suggests that FGFR-1 is important for neuronal cell fate in the adult hippocampus. In human brain, FGF-2 appears to be an important component in the anti-depressive effect of drugs. In summary, FGF2 is an important modulator of the cell fate of neural precursor and, promotes oligodendrogenesis. In this review, we describe the expression pattern of FGFR2 and its role in neural precursors derived from the SVZ and the SGZ.

Neurogenesis in Alzheimer´s disease: a realistic alternative to neuronal degeneration?

Neural stem cells (NSC) are cells that have the capacity to generate multiple types of differentiated brain cells. In conditions in which there is a loss of key functional cell groups, such as neurons, inducing or introducing neural stem cells to replace the function of those cells that were lost during the disease has the greatest potential therapeutic applications. Indeed, the achievement of one of the main objectives of various investigations is already on the horizon for some conditions, such as Alzheimers disease. It is not known whether impaired neurogenesis contributes to neuronal depletion and cognitive dysfunction in Alzheimers disease (AD). The results of the different investigations are controversial; some studies have found that neurogenesis is increased in AD brains, but others have not.

Neural restrictive silencer factor and choline acetyltransferase expression in cerebral tissue of Alzheimer's Disease patients: a pilot study

Decreased Choline Acetyltransferase (ChAT) brain level is one of the main biochemical disorders in Alzheimer’s Disease (AD). In rodents, recent data show that the CHAT gene can be regulated by a neural restrictive silencer factor (NRSF). The aim of the present work was to evaluate the gene and protein expression of CHAT and NRSF in frontal, temporal, entorhinal and parietal cortices of AD patient brains. Four brains from patients with AD and four brains from subjects without dementia were studied. Cerebral tissues were obtained and processed by the guanidine isothiocyanate method for RNA extraction. CHAT and NRSF gene and protein expression were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. CHAT gene expression levels were 39% lower in AD patients as compared to the control group (p < 0.05, U test). ChAT protein levels were reduced by 17% (p = 0.02, U test). NRSF gene expression levels were 86% higher in the AD group (p = 0.001, U test) as compared to the control group. In the AD subjects, the NRSF protein levels were 57% higher (p > 0.05, U test) than in the control subjects. These findings suggest for the first time that in the brain of AD patients high NRSF protein levels are related to low CHAT gene expression levels.

Regulation of neural stem cell in the human SVZ by trophic and morphogenic factors

The subventricular zone (SVZ), lining the lateral ventricular system, is the largest germinal region in mammals. In there, neural stem cells express markers related to astoglial lineage that give rise to new neurons and oligodendrocytes in vivo. In the adult human brain, in vitro evidence has also shown that astrocytic cells isolated from the SVZ can generate new neurons and oligodendrocytes. These proliferative cells are strongly controlled by a number of signals and molecules that modulate, activate or repress the cell division, renewal, proliferation and fate of neural stem cells. In this review, we summarize the cellular composition of the adult human SVZ (hSVZ) and discuss the increasing evidence showing that some trophic modulators strongly control the function of neural stem cells in the SVZ.

Neuroprotective Effects of β-Caryophyllene against Dopaminergic Neuron Injury in a Murine Model of Parkinson’s Disease Induced by MPTP

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders and is characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Although the causes of PD are not understood, evidence suggests that its pathogenesis is associated with oxidative stress and inflammation. Recent studies have suggested a protective role of the cannabinoid signalling system in PD. β-caryophyllene (BCP) is a natural bicyclic sesquiterpene that is an agonist of the cannabinoid type 2 receptor (CB2R). Previous studies have suggested that BCP exerts prophylactic and/or curative effects against inflammatory bowel disease through its antioxidative and/or anti-inflammatory action. The present study describes the neuroprotective effects of BCP in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced murine model of PD, and we report the results of our investigation of its neuroprotective mechanism in neurons and glial cells. In the murine model, BCP pretreatment ameliorated motor dysfunction, protected against dopaminergic neuronal losses in the SN and striatum, and alleviated MPTP-induced glia activation. Additionally, BCP inhibited the levels of inflammatory cytokines in the nigrostriatal system. The observed neuroprotection and inhibited glia activation were reversed upon treatment with the CB2R selective antagonist AM630, confirming the involvement of the CB2R. These results indicate that BCP acts via multiple neuroprotective mechanisms in our murine model and suggest that BCP may be viewed as a potential treatment and/or preventative agent for PD.

Prophylactic Role of Oral Melatonin Administration on Neurogenesis in Adult Balb/C Mice during REM Sleep Deprivation

Purpose. The aim of this study was to assess the effect of melatonin in the proliferation of neural progenitors, melatonin concentration, and antiapoptotic proteins in the hippocampus of adult mice exposed to 96 h REM sleep deprivation (REMSD) prophylactic administration of melatonin for 14 days. Material and Methods. Five groups of Balb/C mice were used: (1) control, (2) REMSD, (3) melatonin (10 mg/kg) plus REMSD, (4) melatonin and intraperitoneal luzindole (once a day at 5 mg/kg) plus REMSD, and (5) luzindole plus REMSD. To measure melatonin content in hippocampal tissue we used HPLC. Bcl-2 and Bcl-xL proteins were measured by Western Blot and neurogenesis was determined by injecting 5-bromo-2-deoxyuridine (BrdU) and BrdU/nestin expressing cells in the subgranular zone of the dentate gyrus were quantified by epifluorescence. Results. The melatonin-treated REMSD group showed an increased neural precursor in 44% with respect to the REMSD group and in 28% when contrasted with the control group (P < 0.021). The melatonin-treated REMSD group also showed the highest expression of Bcl-2 and Bcl-xL as compared to the rest of the groups. Conclusion. The exogenous administration of melatonin restores the tissue levels of sleep-deprived group and appears to be an efficient neuroprotective agent against the deleterious effects of REMSD.