Damage to myelinated axons contributes to neurological deficits after acute CNS injury, including ischemic and hemorrhagic stroke. Potential treatments to promote re-myelination will require fully differentiated oligodendrocytes, but almost nothing is known about their fate following intracerebral hemorrhage (ICH). Using a rat model of ICH in the striatum, we quantified survival, proliferation, and differentiation of oligodendrocyte precursor cells (OPCs) (at 1, 3, 7, 14, and 28 days) in the peri-hematoma region, surrounding striatum, and contralateral striatum. In the peri-hematoma, the density of Olig2+ cells increased dramatically over the first 7 days, and this coincided with disorganization and fragmentation of myelinated axon bundles. Very little proliferation (Ki67+) of Olig2+ cells was seen in the anterior subventricular zone from 1 to 28 days. However, by 3 days, many were proliferating in the peri-hematoma region, suggesting that local proliferation expands their population. By 14 days, the density of Olig2+ cells declined in the peri-hematoma region, and, by 28 days, it reached the low level seen in the contralateral striatum. At these later times, many surviving axons were aligned into white-matter bundles, which appeared less swollen or fragmented. Oligodendrocyte cell maturation was prevalent over the 28-day period. Densities of immature OPCs (NG2+Olig2+) and mature (CC-1+Olig2+) oligodendrocytes in the peri-hematoma increased dramatically over the first week. Regardless of the maturation state, they increased preferentially inside the white-matter bundles. These results provide evidence that endogenous oligodendrocyte precursors proliferate and differentiate in the peri-hematoma region and have the potential to re-myelinate axon tracts after hemorrhagic stroke.

BackgroundChronic neuropathic pain is a common symptom of multiple sclerosis (MS). MOG35–55-induced experimental autoimmune encephalomyelitis (EAE) has been used as an animal model to investigate the mechanisms of pain in MS. Previous studies have implicated sensitization of spinal nociceptive networks in the pathogenesis of pain in EAE. However, the involvement of supraspinal sites of nociceptive integration, such as the primary somatosensory cortex (S1), has not been defined. We therefore examined functional, structural, and immunological alterations in S1 during the early stages of EAE, when pain behaviors first appear.We also assessed the effects of the antidepressant phenelzine (PLZ) on S1 alterations and nociceptive (mechanical) sensitivity in early EAE. PLZ has been shown to restore central nervous system (CNS) tissue concentrations of GABA and the monoamines (5-HT, NA) in EAE. We hypothesized that PLZ treatment would also normalize nociceptive sensitivity in EAE by restoring the balance of excitation and inhibition (E-I) in the CNS.MethodsWe used in vivo flavoprotein autofluorescence imaging (FAI) to assess neural ensemble responses in S1 to vibrotactile stimulation of the limbs in early EAE. We also used immunohistochemistry (IHC), and Golgi-Cox staining, to examine synaptic changes and neuroinflammation in S1. Mechanical sensitivity was assessed at the clinical onset of EAE with Von Frey hairs.ResultsMice with early EAE exhibited significantly intensified and expanded FAI responses in S1 compared to controls. IHC revealed increased vesicular glutamate transporter (VGLUT1) expression and disrupted parvalbumin+ (PV+) interneuron connectivity in S1 of EAE mice. Furthermore, peri-neuronal nets (PNNs) were significantly reduced in S1. Morphological analysis of excitatory neurons in S1 revealed increased dendritic spine densities. Iba-1+ cortical microglia were significantly elevated early in the disease. Chronic PLZ treatment was found to normalize mechanical thresholds in EAE. PLZ also normalized S1 FAI responses, neuronal morphologies, and cortical microglia numbers and attenuated VGLUT1 reactivity—but did not significantly attenuate the loss of PNNs.ConclusionsThese findings implicate a pro-excitatory shift in the E-I balance of the somatosensory CNS, arising early in the pathogenesis EAE and leading to large-scale functional and structural plasticity in S1. They also suggest a novel antinociceptive effect of PLZ treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0609-4) contains supplementary material, which is available to authorized users.

Rehabilitation is an effective behavioral and neuroprotective strategy for ICH. Neither effect appears to stem from influencing iron toxicity or inflammation. Thus, additional work must identify underlying mechanisms to help further therapeutic gains.

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Iron chelators, such as the intracellular ferrous chelator 2,2'-bipyridine, are a potential means of ameliorating iron-induced injury after intracerebral hemorrhage (ICH). We evaluated bipyridine against the collagenase and whole-blood ICH models and a simplified model of iron-induced damage involving a striatal injection of FeCl2 in adult rats. First, we assessed whether bipyridine (25 mg/kg beginning 12 h post-ICH and every 12 h for 3 days) would attenuate non-heme iron levels in the brain and lessen behavioral impairments (neurological deficit scale, corner turn test, and horizontal ladder) 7 days after collagenase-induced ICH. Second, we evaluated bipyridine (20 mg/kg beginning 6 h post-ICH and then every 24 h) on edema 3 days after collagenase infusion. Body temperature was continually recorded in a subset of these rats beginning 24 h prior to ICH until euthanasia. Third, bipyridine was administered (as per experiment 2) after whole-blood infusion to examine tissue loss, neuronal degeneration, and behavioral impairments at 7 days post-stroke, as well as body temperature for 3 days post-stroke. Finally, we evaluated whether bipyridine (25 mg/kg given 2 h prior to surgery and then every 12 h for 3 days) lessens tissue loss, neuronal death, and behavioral deficits after striatal FeCl2 injection. Bipyridine caused a significant hypothermic effect (maximum drop to 34.6 °C for 2-5 h after each injection) in both ICH models; however, in all experiments bipyridine-treated rats were indistinguishable from vehicle controls on all other measures (e.g., tissue loss, behavioral impairments, etc.). These results do not support the use of bipyridine against ICH.

Background: Brain injury after intracerebral hemorrhage (ICH) arises from numerous contributors, of which some also play essential roles. Notably, thrombin production, needed to stop bleeding, also causes acute cell death and edema. In some rodent models of ICH, peri-hematoma neurons die over weeks. Hence we evaluated whether thrombin is responsible for this chronic degeneration. Functional impairments after ICH also result from sub-lethal damage to neurons, especially the loss of dendrites. Thus, we evaluated whether thrombin infusion alone, a reductionist model of ICH, causes similar injury. Methods: Adult rats had a modest intra-striatal infusion of thrombin (1 U) or saline followed by a behavioral test, to verify impairment, 7 days later. After this they were euthanized and tissue stained with Golgi-Cox solution to allow the assessment of dendritic morphology in striatal neurons. In a second experiment, rats survived 7 or 60 days after thrombin infusion in order to histologically determine lesion volume. Results: Thrombin caused early cell death and considerable atrophy in surviving peri-lesion neurons, which had less than half of their usual numbers of branches. However, total tissue loss was comparable at 7 (24.1 mm 3 ) and 60 days (25.6 mm 3 ). Conclusion: Thrombin infusion causes early cell death and neuronal atrophy in nearby surviving striatal neurons but thrombin does not cause chronic tissue loss. Thus, the chronic degeneration found after ICH in rats is not simply and solely due to acute thrombin production. Nonetheless, thrombin is an important contributor to behavioral dysfunction because it causes cell death and substantial dendritic injury.RÉSUMÉ: La thrombine cause une atrophie neuronale et une mort cellulaire aiguë mais ne cause pas de mort cellulaire chronique. Contexte: De nombreuses variables contribuent, parfois d'une manière essentielle, à l'étendue des effets au cerveau à la suite d'une hémorragie intra-cérébrale (HIC). Notamment la production de thrombine, nécessaire pour arrêter le saignement, provoque également la mort cellulaire aiguë et l'oedème. Dans certains modèles d'HIC du rongeur, les neurones péri-hématomes meurent au cours des semaines. Par conséquent nous avons évalué si la thrombine est responsable de la dégénérescence chronique. Des déficiences fonctionnelles suivant une HIC entraînent également des effets sublétaux chez les neurones, surtout la perte des dendrites. Ainsi nous avons testé si la thrombine seule cause un effet similaire. Méthodes: Nous avons administré aux rats adultes une infusion intra-striatale modeste ou de thrombine (1 U) ou d'une solution saline, avec un test de comportement sept jours plus tard pour vérifier la déficience. Ils ont étaient euthanasiés et nous avons fait une évaluation morphologique des neurones striataux, suivant l'imprégnation avec la méthode de Golgi-Cox. Dans une autre expérience, les rats qui ont survécu entre 7 ou 60 jours après l'infusion de thrombine afin de déterminer le volume des lésions histologiques. Résultats: La...

Background — After an intracerebral hemorrhage (ICH) iron is released from degrading erythrocytes over days, which causes secondary damage by increasing free radicals. Many studies show that iron chelators, such as deferoxamine, lessen injury, but not all studies support this. Hypothesis — The ferrous iron chelator, 2,2 Dipyridyl (DP), will decrease injury after ICH or intraparenchymal FeCl 2 infusion in rats. Experiment 1— Rats were given a collagenase-induced striatal ICH. In experiments 1 and 3, we tested whether behavior was improved (e.g., walking) from administering DP (25mg/kg/day, 12 hours after surgery for 3 days). They were euthanized after 7 days to determine non-heme iron levels in the brain. Experiment 2— Rats were injected with DP (20mg/kg) 6 hours after collagenase infusion and every 24 hours till euthanasia at 3 days for measuring edema. Experiment 3— After injecting FeCl 2 in the striatum rats were given DP (25mg/kg every 12 hr starting 2 hours prior to surgery for 3 days). The volume of tissue loss and Fluoro-jade staining (degenerating neurons) was measured. Results — DP did not improve behavioral or histological outcome or reduce edema in either the collagenase ICH or FeCl 2 model. DP also did not affect parenchymal non-heme iron level. Conclusion — Our data suggests that DP on its own is not an effective strategy for ICH.

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