Download the Free Unbound MEDLINE PubMed App to your smartphone or tablet.
Available for iPhone, iPad, iPod touch, and Android.
Experimental neurology [journal]
- A re-assessment of long distance growth and connectivity of neural stem cells after severe spinal cord injury. [JOURNAL ARTICLE]
- Exp Neurol 2014 Apr 17.
As part of the NIH "Facilities of Research Excellence-Spinal Cord Injury" project to support independent replication, we repeated key parts of a study reporting robust engraftment of neural stem cells (NSCs) treated with growth factors after complete spinal cord transection in rats. Rats (n=20) received complete transections at thoracic level 3 (T3) and 2weeks later received NSC transplants in a fibrin matrix with a growth factor cocktail using 2 different transplantation methods (with and without removal of scar tissue). Control rats (n=9) received transections only. Hindlimb locomotor function was assessed with the BBB scale. Nine weeks post injury, reticulospinal tract axons were traced in 6 rats by injecting BDA into the reticular formation. Transplants grew to fill the lesion cavity in most rats although grafts made with scar tissue removal had large central cavities. Grafts blended extensively with host tissue obliterating the astroglial boundary at the cut ends, but in most cases there was a well-defined partition within the graft that separated rostral and caudal parts of the graft. In some cases, the partition contained non-neuronal scar tissue. There was extensive outgrowth of GFP labeled axons from the graft, but there was minimal ingrowth of host axons into the graft revealed by tract tracing and immunocytochemistry for 5HT. There were no statistically significant differences between transplant and control groups in the degree of locomotor recovery. Our results confirm the previous report that NSC transplants can fill lesion cavities and robustly extend axons, but reveal that most grafts do not create a continuous bridge of neural tissue between rostral and caudal segments.
- Sex differences in human epilepsy. [REVIEW]
- Exp Neurol 2014 Apr 16.
In the majority of neuropsychiatric conditions, marked gender-based differences have been found in the epidemiology, clinical manifestations, and therapy of disease. Emerging data suggest that gender differences exist also in the epidemiology, and pathophysiology of epilepsy. The present review summarizes the current information regarding gender and epilepsy. These differences are regarded from the perspective of innate sex differences in cerebral morphology, structural and functional connections, and assuming that these differences may render men and women differently vulnerable to epileptogenicity.
- G-protein coupled receptor 6 deficiency alters striatal dopamine and cAMP concentrations and reduces dyskinesia in a mouse model of Parkinson´s disease. [JOURNAL ARTICLE]
- Exp Neurol 2014 Apr 16.
The orphan G-protein coupled receptor 6 (GPR6) is a constitutively active receptor which is positively coupled to the formation of cyclic adenosine-3',5'-monophosphate (cAMP). GPR6 is predominantly expressed in striatopallidal neurons. Here, we investigated neurochemical and behavioural effects of Gpr6 deficiency in mice. Gpr6 depletion decreased in vivo cAMP tissue concentrations (20%) in the striatum. An increase of striatal tissue dopamine concentrations (10%) was found in Gpr6(-/-) mice, whereas basal extracellular dopamine levels were not changed compared with Gpr6(+/+m)ice, as shown by in vivo microdialysis. Western blot analyses revealed no alteration in the expression and subcellular localisation of the dopamine D2 receptor in the striatum of Gpr6(-/-) mice, and the number of tyrosine hydroxylase positive neurons in the substantia nigra was unchanged. DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32kDA) expression in the striatum of Gpr6(-/-) mice was not altered, however, a twofold increase in the phosphorylation of DARPP-32 at Thr34 was detected in Gpr6(-/-) compared with Gpr6(+/+m)ice. Gpr6(-/-) mice showed higher locomotor activity in the open field, which persisted after treatment with the dopamine D2 receptor antagonist haloperidol. They also displayed reduced abnormal involuntary movements after apomorphine and quinpirole treatment in the mouse dyskinesia model of Parkinson´s disease. In conclusion, the depletion of Gpr6 reduces cAMP concentrations in the striatum and alters the striatal dopaminergic system. Gpr6 deficiency causes an interesting behavioural phenotype in the form of enhanced motor activity combined with reduced abnormal involuntary movements. These findings could offer an opportunity for treatment of Parkinson's disease beyond dopamine replacement.
- Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease. [JOURNAL ARTICLE]
- Exp Neurol 2014 Apr 16.
Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, studies of post-mortem PD brains have shown that not only DA neurons but also the noradrenergic (NA) neurons in the locus coeruleus degenerate, and that the NA neurodegeneration may be as profound, and also precede degeneration of the midbrain DA neurons. Previous studies in animal models of PD have suggested that loss of forebrain NA will add to the development of motor symptoms in animals with lesions of the nigrostriatal DA neurons, but the results obtained in rodents have been inconclusive due to the shortcomings of the toxin, DSP-4, used to lesion the NA projections. Here, we have developed an alternative double-lesion paradigm using injections of 6-OHDA into striatum in combination with intraventricular injections of a powerful NA immunotoxin, anti-DBH-Saporin, to eliminate the NA neurons in the locus coeruleus, and associated pontine nuclei. Animals with combined DA and NA lesions were more prone to develop L-DOPA-induced dyskinesia, even at low L-DOPA doses, and they performed significantly worse in tests of reflexive and skilled paw use, the stepping and staircase tests, compared to DA-only lesioned rats. Post-mortem analysis revealed that NA depletion did not affect the degree of DA depletion, or the loss of tyrosine hydroxylase-positive innervation in the striatum. Cell loss in the substantia nigra was similar in both single and double lesioned animals, showing that the worsening effect was not due to increased loss of nigral DA neurons. The results show that damage to brainstem NA neurons, contributes to the development of motor impairments and the appearance of L-DOPA-induced dyskinesia in 6-OHDA lesioned rats, and provide support for the view that the development of motor symptoms and dyskinetic side effects in PD patients reflects the combined loss of midbrain DA neurons and NA neurons.
- Neuroprotective dimethyl fumarate synergizes with immunomodulatory interferon beta to provide enhanced axon protection in autoimmune neuroinflammation. [JOURNAL ARTICLE]
- Exp Neurol 2014 Apr 13.
Despite recent advances in development of treatments for multiple sclerosis, there is still an unmet need for more effective and also safe therapies. Based on the modes of action of interferon-beta (IFN-β) and dimethyl fumarate (DMF), we hypothesized that anti-inflammatory and neuroprotective effects may synergize in experimental autoimmune encephalomyelitis (EAE).EAE was induced in C57BL/6 mice by immunization with MOG35-55-peptide. Murine IFN-β was injected s.c. every other day at 10.000IU, and DMF was provided at 15mg/kg by oral gavage twice daily. Control mice received PBS injections and were treated by oral gavage with the vehicle methylcellulose. Mice were scored daily by blinded observers and histological, FACS and cytokine studies were performed to further elucidate the underlying mechanism of action.Combination therapy significantly ameliorated EAE disease course in comparison to controls and monotherapy with IFN-β. Histological analyses showed a significant effect on axon preservation with almost twice as much axons present in inflamed lesions as compared to control. Remarkably, the effect on axonal preservation was more pronounced under combination therapy than with both monotherapies. Neither monotherapy nor combination therapy demonstrated modulation of cytokines and frequency of antigen presenting cells.Combination of IFN-β and DMF resulted in greater beneficial effects with improved tissue protection as compared to the respective monotherapies. Further combination studies of these safe therapies in human disease are warranted.
- The neuroanatomy of sexual dimorphism in opioid analgesia. [REVIEW]
- Exp Neurol 2014 Apr 13.
The influence of sex has been neglected in clinical studies on pain and analgesia, with the vast majority of research conducted exclusively in males. However, both preclinical and clinical studies indicate that males and females differ in both the anatomical and physiological composition of central nervous system circuits that are involved in pain processing and analgesia. These differences influence not only the response to noxious stimuli, but also the ability of pharmacological agents to modify this response. Morphine is the most widely prescribed opiate for the alleviation of persistent pain in the clinic; however, it is becoming increasingly clear that morphine is less potent in women compared to men. This review highlights recent research identifying neuroanatomical and physiological dimorphisms underlying sex differences in pain and opioid analgesia, focusing on the endogenous descending pain modulatory circuit.
- Glial cell line-derived neurotrophic factor promotes increased phenotypic marker expression in femoral sensory and motor-derived Schwann cell cultures. [JOURNAL ARTICLE]
- Exp Neurol 2014 Apr 13.
Schwann cells (SCs) secrete growth factors and extracellular matrix molecules that promote neuronal survival and help guide axons during regeneration. Transplantation of SCs is a promising strategy for enhancing peripheral nerve regeneration. However, we and others have shown that after long-term in vitro expansion, SCs revert to a de-differentiated state similar to the phenotype observed after injury. In vivo, glial cell-line derived neurotrophic factor (GDNF) may guide the differentiation of SCs to remyelinate regenerating axons. Therefore, we hypothesized that exogenous GDNF may guide the differentiation of SCs into their native phenotypes in vitro through stimulation of GDNF family receptor (GFR)α-1. When activated in SCs, GFRα-1 promotes phosphorylation of Fyn, a Src family tyrosine kinase responsible for mediating downstream signaling for differentiation and proliferation. In this study, SCs harvested from the sensory and motor branches of rat femoral nerve were expanded in vitro and then cultured with 50 or 100ng/mL of GDNF. The exogenous GDNF promoted differentiation of sensory and motor-derived SCs back to their native phenotypes, as demonstrated by decreased proliferation after 7days and increased expression of S100Ββ and phenotype-specific markers. Furthermore, inhibiting Fyn with Src family kinase inhibitors, PP2 and SU6656, and siRNA-mediated knockdown of Fyn reduced GDNF-stimulated differentiation of sensory and motor-derived SCs. These results demonstrate that activating Fyn is necessary for GDNF-stimulated differentiation of femoral nerve-derived SCs into their native phenotypes in vitro. Therefore GDNF could be incorporated into SC-based therapies to promote differentiation of SCs into their native phenotype to improve functional nerve regeneration.
- Laquinimod, an upcoming oral immunomodulatory agent for treatment of multiple sclerosis. [REVIEW]
- Exp Neurol 2014 Apr 13.
Laquinimod is a novel oral drug that is currently being evaluated for the treatment of relapsing-remitting multiple sclerosis (RRMS). Although the mode of action of laquinimod remains to be fully elucidated, current knowledge indicates that laquinimod exerts beneficial activities both on the peripheral immune system and within the central nervous system (CNS). The immunomodulatory properties have been deciphered primarily from studies of laquinimod in the animal model of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Data indicate that laquinimod has a primary effect on innate immunity. Laquinimod modulates the function of various myeloid antigen presenting cell populations, which then downregulate proinflammatory T cell responses. Further, data also indicate that laquinimod acts directly on resident cells within the CNS to reduce demyelination and axonal damage. Results from clinical trials that tested laquinimod in RRMS demonstrated that it reduced relapse rate and the mean cumulative number of active lesions, and had a more marked reduction in disability progression than the relapse rate. Laquinimod treatment was associated with an excellent safety and tolerability profile. These data indicate that laquinimod will offer a valuable new treatment option for RRMS patients.
- Galanin promotes neuronal differentiation from neural progenitor cells in vitro and contributes to the generation of new olfactory neurons in the adult mouse brain. [JOURNAL ARTICLE]
- Exp Neurol 2014 Apr 11.
Galanin is a pleiotropic neuropeptide widely expressed in the nervous system. It plays a role in many diverse physiological functions - including nociception, cognition and metabolism regulation - and acts as neurotrophic/neuroprotective factor for several neuronal populations. In this article we sought to determine the role of galanin on neural stem cell function and its contribution to the plasticity of the nervous system. Here we show that galanin and its receptors are expressed in neural progenitor cells (NPCs) isolated from the developing striatum. Stimulation with galanin results in upregulation of Bcl-Xl, Bcl-2, Mash-1 and Olig-2 that are part of well known pro-survival/pro-neuronal signalling pathways. Accordingly, treatment with galanin increases the number of neurons upon differentiation from these progenitors. We then show that these effects are recapitulated in NPCs isolated from the adult subventricular zone (SVZ), where galanin increases the total number of neurons and the number of newly-generated neurons upon differentiation in vitro. The significance of these findings is highlighted in the adult brain where loss of galanin leads to a marked decrease in the rate of adult SVZ neurogenesis and a reduction in the number of newly generated cells in the olfactory bulb. Interestingly, Gal-KO mice display normal performances in simple tasks of olfactory detection and discrimination, which points to the existence of a certain degree of redundancy in SVZ neurogenesis. Our findings establish the role of galanin as a modulator of neural stem cell function and support the importance of galanin for brain plasticity and repair.