Journal of neurochemistry
-
Journal of neurochemistry · May 2008
Excitotoxic damage, disrupted energy metabolism, and oxidative stress in the rat brain: antioxidant and neuroprotective effects of L-carnitine.
Excitotoxicity and disrupted energy metabolism are major events leading to nerve cell death in neurodegenerative disorders. These cooperative pathways share one common aspect: triggering of oxidative stress by free radical formation. In this work, we evaluated the effects of the antioxidant and energy precursor, levocarnitine (L-CAR), on the oxidative damage and the behavioral, morphological, and neurochemical alterations produced in nerve tissue by the excitotoxin and free radical precursor, quinolinic acid (2,3-pyrindin dicarboxylic acid; QUIN), and the mitochondrial toxin, 3-nitropropionic acid (3-NP). ⋯ Morphological alterations produced by both toxins (increased striatal glial fibrillary acidic protein-immunoreactivity for QUIN and enhanced neuronal damage in different brain regions for 3-NP) were reduced by L-CAR. In addition, L-CAR prevented the synergistic action of 3-NP and QUIN to increase motor asymmetry and depleted striatal GABA levels. Our results suggest that the protective properties of L-CAR in the neurotoxic models tested are mostly mediated by its characteristics as an antioxidant agent.
-
Journal of neurochemistry · May 2008
Gabapentin produces PKA-dependent pre-synaptic inhibition of GABAergic synaptic transmission in LC neurons following partial nerve injury in mice.
We have previously demonstrated that gabapentin supraspinally activates the descending noradrenergic system to ameliorate pain hypersensitivity in mice with partial nerve ligation. To clarify the supraspinal mechanism of action of gabapentin, whole-cell patch-clamp recordings were performed on locus coeruleus (LC) neurons in brainstem slices prepared from mice after peripheral nerve injury or mice subjected to a sham-operation, and the effects of gabapentin in the modulation of synaptic transmission were studied. Bath application of gabapentin (10, 30 and 100 muM) in a concentration-dependent manner reduced the GABA(A) receptor-mediated inhibitory post-synaptic currents (IPSCs) in slices prepared from partially nerve-ligated mice, whereas glutamate-mediated excitatory post-synaptic currents were hardly affected. ⋯ As the protein kinase A (PKA) inhibitor H-89 but not the protein kinase C inhibitor chelerythrine abolished the inhibitory action of gabapentin on IPSCs, PKA-mediated phosphorylation seems to be important for supraspinal gabapentin responsiveness in neuropathic conditions. Together, gabapentin generates PKA-dependent pre-synaptic inhibition of GABAergic synaptic transmission, and thereby removes the inhibitory influence on LC neurons only under neuropathic pain states. These findings provide crucial evidence of how supraspinally acting gabapentin recruits the descending noradrenergic system.
-
Journal of neurochemistry · May 2008
Metabolic changes detected by proton magnetic resonance spectroscopy in vivo and in vitro in a murin model of Parkinson's disease, the MPTP-intoxicated mouse.
Parkinson's disease is a neurodegenerative disorder characterized by the progressive loss of the dopaminergic neurons in the substantia nigra pars compacta, which project to the striatum. The aim of this study was to analyze in vivo and in vitro consequences of dopamine depletion on amount of metabolites in a mouse model of Parkinson's disease using proton (1)H magnetic resonance spectroscopy (MRS). The study was performed on control mice (n = 7) and MPTP-intoxicated mice (n = 7). ⋯ The in vitro results confirmed these results, Glu (10.9 +/- 2.5 vs. 7.9 +/- 1.7 micromol/g, p < 0.05), Gln (6.8 +/- 2.9 vs. 4.3 +/- 1.0 micromol/g, p < 0.05), and GABA (2.9 +/- 0.9 vs. 1.5 +/- 0.4 micromol/g, p < 0.01). The present study strongly supports a hyperactivity of the glutamatergic cortico-striatal pathway hypothesis after dopaminergic denervation in association with an increase of striatal GABA levels. It further shows an increased of striatal Gln concentrations, perhaps as a strategy to protect neurons from Glu excitotoxic injury after striatal dopamine depletion.
-
Journal of neurochemistry · May 2008
Comparative StudyOsmotic swelling characteristics of glial cells in the murine hippocampus, cerebellum, and retina in situ.
Glial cells are proposed to play a major role in the ionic and osmotic homeostasis in the CNS. Swelling of glial cells contributes to the development of edema in neural tissue under pathological conditions such as trauma and ischemia. In this study, we compared the osmotic swelling characteristics of murine hippocampal astrocytes, cerebellar Bergmann glial cells, and retinal Müller glial cells in acutely isolated tissue slices in response to hypoosmotic stress and pharmacological blockade of Kir channels. ⋯ Blockade of Kir channels under hypoosmotic conditions induced an immediate and strong swelling in Müller cell somata, but had no cumulative effect to brain astroglial somata. No regulatory volume decrease could be observed in all cell types. The data suggest that Kir channels are differently implicated in cell volume homeostasis of retinal Müller cells and brain astrocytes and that Müller cells and brain astrocytes differ in their osmotic swelling properties.
-
The role of water channel aquaporin 1 (AQP-1) in uninjured or injured spinal cords is unknown. AQP-1 is weakly expressed in neurons and gray matter astrocytes, and more so in white matter astrocytes in uninjured spinal cords, a novel finding. As reported before, AQP-1 is also present in ependymal cells, but most abundantly in small diameter sensory fibers of the dorsal horn. ⋯ Interestingly; AQP-1 levels were not affected by long-lasting hypertonicity that significantly increased astrocytic AQP-4, suggesting that the primary role of AQP-1 is not regulating isotonicity in spinal cords. Based on our results we propose possible novel roles for AQP-1 in the injured spinal cords: (i) in neuronal and astrocytic swelling, as AQP-1 was increased in all surviving neurons and reactive astrocytes after SCI and (ii) in the development of the neuropathic pain after SCI. We have shown that decreased AQP-1 in melatonin-treated SCI rats correlated with decreased AQP-1 immunolabeling in the dorsal horns sensory afferents, and with significantly decreased mechanical allodynia, suggesting a possible link between AQP-1 and chronic neuropathic pain after SCI.