Inhibition of Notch1 Signal Promotes Brain Recovery by Modulating Glial Activity

BackgroundNotch1 signaling inhibiton with N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butylester] (DAPT) treatment could promote brain recovery and the intervention effect is different between striatum (STR) and cortex (CTX), which might be accounted for changed glial activities but the in-depth mechanism is still unknown. The purpose of this study was to identify whether DAPT could modulate microglial subtype shifts and astroglial-endfeet aquaporin-4 (AQP4) mediated waste solute drainage.MethodsSprague-Dawley rats (n=10) were subjected to 90min of middle cerebral artery occlusion (MCAO) and were treated with DAPT (n=5) or act as control with no treatment (n=5). Two groups of rats underwent MRI scans at 24h and 4 week following stroke, and sacrificed at 4 week after stroke for immunofluorescence (IF).ResultsCompared with control rats, MRI data showed brain recovery in ipsilateral STR but not CTX. And IF showed decreased pro-inflammatory M1 microglia and increased anti-inflammatory M2 microglia in striatal lesion core and peri-lesions of STR, CTX. Meanwhile, IF showed decreased AQP4 polarity in ischemic brain tissue, however, AQP4 polarity in striatal peri-lesions of DAPT treated rats was higher than that in control rats but shows no difference in cortical peri-lesions between control and treated rats. ConclusionsThe present study indicated that DAPT could promote protective microglia subtype shift and striatal astrocyte mediated waste solute drainage.

Neuroinflammation-Induced Upregulation of Glial Cathepsin X Expression and Activity in vivo

Neuroinflammation is an important factor in the pathogenesis of neurodegenerative diseases. Microglia-derived lysosomal cathepsins have been increasingly recognized as important inflammatory mediators that trigger signaling pathways that aggravate neuroinflammation. In vitro, a contribution to neuroinflammation processes has been shown for cathepsin X: however, the expression patterns and functional role of cathepsin X in neuroinflammatory brain pathology remain elusive. In this study we analyzed the expression, activity, regional distribution and cellular localization of cathepsin X in the rat brain with neuroinflammation-induced neurodegeneration. The unilateral injection of lipopolysaccharide (LPS) induced a strong upregulation of cathepsin X expression and its activity in the ipsilateral striatum. In addition to the striatum, cathepsin X overexpression was detected in other brain areas such as the cerebral cortex, corpus callosum, subventricular zone and external globus pallidus, whereas the upregulation was mainly restricted to activated microglia and reactive astrocytes. Continuous administration of the cathepsin X inhibitor AMS36 indicated protective effects against LPS-induced striatal degeneration, as seen by the attenuated LPS-mediated dilation of the lateral ventricles and partial decreased extent of striatal lesion. Taken together, our results indicate that cathepsin X plays a role as a pathogenic factor in neuroinflammation-induced neurodegeneration and represents a potential therapeutic target for neurodegenerative diseases associated with neuroinflammation.

Neuroprotective effect of ACTH on collagenase-induced peri-intraventricular hemorrhage in newborn male rats

Peri-intraventricular hemorrhage (PIVH) is a common and serious prematurity-related complication in neonates. Adrenocorticotropic hormone (ACTH) has neuroprotective actions and is a candidate to ameliorate brain damage following PIVH. Here, we tested the efficacy of ACTH1-24 on a collagenase-induced lesion of the germinal matrix (GM) in newborn male rats. Animals received microinjection of the vehicle (PBS, 2 µl) or collagenase type VII (0.3 IU) into the GM/periventricular tissue on postnatal day (PN) 2. Twelve hours later pups received microinjection of either the agonist ACTH1-24 (0.048 mg/kg), or the antagonist SHU9119 (antagonist of MCR3/MCR4 receptors, 0.01 mg/kg), or their combination. Morphological outcomes included striatal injury extension, neuronal and glial cells counting, and immunohistochemical expression of brain lesion biomarkers ipsilateral and contralateral to the hemorrhagic site. Data were evaluated on PN 8. Collagenase induced PIVH and severe ipsilateral striatal lesion. ACTH1-24 dampened the deleterious effects of collagenase-induced hemorrhage in significantly reducing the extension of the damaged area, the striatal neuronal and glial losses, and the immunoreactive expression of the GFAP, S100β, and NG2-glia biomarkers in the affected periventricular area. SHU9119 blocked the glial density rescuing effect of ACTH1-24. ACTH1-24 could be further evaluated to determine its suitability for preclinical models of PVH in premature infants.

Exaggerated mitophagy: a weapon of striatal destruction in the brain?

Mechanisms responsible for neuronal vulnerability in the brain remain unclear. Striatal neurons are preferentially damaged by 3-nitropropionic acid (3-NP), a mitochondrial complex-II inhibitor, causing striatal damage reminiscent of Huntington's disease (HD), but the mechanisms of the selectivity are not as well understood. We have discovered that Rhes, a protein enriched in the striatum, removes mitochondria via the mitophagy process. The process becomes intensified in the presence of 3-NP, thereby eliminating most of the mitochondria from the striatum. We put forward the hypothesis that Rhes acts as a ‘mitophagy ligand' in the brain and promotes mitophagy via NIX, a mitophagy receptor. Since Rhes interacts and promotes toxicity in association with mutant huntingtin (mHTT), the genetic cause of HD, it is tempting to speculate on whether the exaggerated mitophagy may be a contributing factor to the striatal lesion found in HD. Thus, Rhes-mediated exaggerated mitophagy may act as a weapon of striatal destruction in the brain.

HEMICHOREA/HEMIBALISMUS DENGAN HIPERGLIKEMIA NONKETOTIK PADA STROKE ISKEMIK AKUT

HEMICHOREA/HEMIBALLISM ASSOCIATED WITH NONKETOTIC HYPERGLYCEMIC ON ACUTE ISCHEMIC STROKEABSTRACTHemichorea/hemiballism (HCHB) associated with nonketotic hyperglycemia in acute ischemic stroke is a well-recognized syndrome characterized by the sudden occurrence of hemichorea or more severe expression like hemiballism. The hyperkinetic movements involve the face, arm, or leg. HCHB in acute ischemic stroke is a movement disorder that is rarely reported with hyperkinetic movement. This case report aimed to describe patient with HCHB associated with hyperglycemia as prior sign of stroke ischemic and propose a possible pathophysiology. We report three patients who had HCHB accompanied by hemiparesis, facial and hypoglossus nerve palsy. Laboratory results showed increased serum glucose levels and negative urine ketones. Imaging findings of head CT scan found an infarction in the basal ganglia. Patients are treated with antiplatelet and or anticoagulant therapy and correction of hyperglycemia with additional therapy of dopamine receptor antagonistThe combination of a recent or old striatal lesion and hyperglycemia induce HCHB, causing increased inhibition of the subthalamic nucleus and causing decreased GABAergic inhibition of the thalamus. Diabetes mellitus should always be suspected in patients who develop HCHB movements. When hyperglycemia is detected and treated, movement disorders resolve within a few days and the administration of dopamine receptor antagonists can be considered.Keywords: Hemiballism, hemichorea, hyperglycemia, ischemic strokeABSTRAKHemichorea/hemibalismus (HCHB) yang berhubungan dengan hiperglikemia nonketotik pada stroke iskemik akut adalah sindrom yang ditandai oleh munculnya hemichorea yang terjadi secara tiba-tiba atau disertai dengan gejala yang lebih berat, seperti hemibalismus. Pergerakan hiperkinetik meliputi wajah, lengan dan tungkai. HCHB pada stroke iskemik akut merupakan gangguan pergerakan hiperkinetik yang jarang dilaporkan. Laporan kasus ini bertujuan untuk menggambarkan pasien yang mengalami keluhan HCHB sebagai gejala awal terjadinya stroke iskemik disertai dengan hiperglikemia dan memperkirakan penjelasan patofisiologi yang mungkin terjadi pada pasien ini. Kami melaporkan tiga pasien dengan keluhan HCHB sebagai gejala awal stroke iskemik akut yang disertai hiperglikemia. Pada ketiga kasus tersebut keluhan disertai dengan paresis nervus fasialis, hipoglossus serta hemiparesis ekstremitas kontralateral lesi. Kadar glukosa serum meningkat dan keton urin negatif. Gambaran CT scan menunjukkan adanya infark di ganglia basalis. Pada tata laksana kami menemukan bahwa koreksi hiperglikemi disertai pemberian terapi antikoagulan dan atau antiplatelet serta agen neuroleptik dapat menyebabkan perbaikan luaran pada gejala HCHB secara perlahan. Kombinasi lesi striatal baru dan hiperglikemia dapat menginduksi terjadinya HCHB karena kedua hal tersebut dapat menyebabkan peningkatan inhibisi inti subtalamik dan gangguan inhibisi GABAergic talamus. Diabetes melitus harus selalu dicurigai pada pasien dengan keluhan HCHB. Ketika hiperglikemia terdeteksi dan ditatalaksana, gangguan gerakan menghilang dalam beberapa hari dan dapat dipertimbangkan dengan pemberian terapi neuroleptik.Kata kunci: Hemibalismus, hemichorea, hiperglikemia, stroke iskemik

Rhes, a striatal-enriched protein, promotes mitophagy via Nix

Elimination of dysfunctional mitochondria via mitophagy is essential for cell survival and neuronal functions. But, how impaired mitophagy participates in tissue-specific vulnerability in the brain remains unclear. Here, we find that striatal-enriched protein, Rhes, is a critical regulator of mitophagy and striatal vulnerability in brain. In vivo interactome and density fractionation reveal that Rhes coimmunoprecipitates and cosediments with mitochondrial and lysosomal proteins. Live-cell imaging of cultured striatal neuronal cell line shows Rhes surrounds globular mitochondria, recruits lysosomes, and ultimately degrades mitochondria. In the presence of 3-nitropropionic acid (3-NP), an inhibitor of succinate dehydrogenase, Rhes disrupts mitochondrial membrane potential (ΔΨm) and promotes excessive mitophagy and cell death. Ultrastructural analysis reveals that systemic injection of 3-NP in mice promotes globular mitochondria, accumulation of mitophagosomes, and striatal lesion only in the wild-type (WT), but not in the Rhes knockout (KO), striatum, suggesting that Rhes is critical for mitophagy and neuronal death in vivo. Mechanistically, Rhes requires Nix (BNIP3L), a known receptor of mitophagy, to disrupt ΔΨm and promote mitophagy and cell death. Rhes interacts with Nix via SUMO E3-ligase domain, and Nix depletion totally abrogates Rhes-mediated mitophagy and cell death in the cultured striatal neuronal cell line. Finally, we find that Rhes, which travels from cell to cell via tunneling nanotube (TNT)-like cellular protrusions, interacts with dysfunctional mitochondria in the neighboring cell in a Nix-dependent manner. Collectively, Rhes is a major regulator of mitophagy via Nix, which may determine striatal vulnerability in the brain.

Subcortical Lesions Impact Confrontation Naming in Bilinguals with Later Age of Acquisition

Objective Multilinguals show greater subcortical activation during language tasks than monolinguals. Among multilinguals, prior studies found later age of acquisition (AoA) of a second language in association with more diffuse, non-traditional language representation. While such findings have clear clinical implications, little research has examined relationships among linguistic history, neuroanatomical integrity, and language skills in a clinical population. This study examined relationships between subcortical lesions and confrontation naming in strong bilinguals who acquired English (L2) later in life compared to those with earlier AoA. Participants and Method Forty-two bilinguals with Spanish as a first language (English L2) were selected from a database of veterans referred for clinical neuropsychological evaluation (M Age = 64 years; M Education = 12 years; 93% men). They reported strong bilingualism after L2 acquisition (M AoA = 10 years), with current English preference. Twenty-nine had neuroimaging, which was coded on a 4-point ordinal scale for lesion burden in white matter and striatum. Moderation models were tested for interaction between AoA and subcortical lesions in bilinguals using different L2 naming outcomes, controlling for age, education, occupation, and English fluency (i.e., Test of Premorbid Functioning). Results Moderation showed significant interaction of AoA with striatal lesion burden for scores on all naming tests, with a similar but less robust relationship between white matter lesions and naming outcomes. Graphical analysis revealed subcortical lesions had a negative impact on naming scores in those with later L2 AoA. Conclusions Results suggest “atypical” subcortical involvement in naming is more likely for bilinguals who acquired L2 later. While clinicians typically associate impaired naming with temporal lobe dysfunction, findings suggest subcortical dysfunction should be considered among bilinguals with later L2 AoA.

Therapeutic potential of inhibition of the neuroinflammation induced cathepsin X: in vivo evidence

Parkinson’s disease (PD) is a progressive neurodegenerative disorder with unknown cause, but it has been postulated that chronic neuroinflammation may play a role in its pathogenesis. Microglia-derived lysosomal cathepsins have been increasingly recognized as important inflammatory mediators. Here, we analyzed the regional distribution and cellular localization of the cathepsin X in the rat brain with neuroinflammation-induced neurodegeneration. Unilateral injection of lipopolysaccharide (LPS) into the striatum induced strong upregulation of cathepsin X expression and its activity in the ipsilateral striatum. In addition to the striatum, cathepsin X overexpression was detected in other areas such as cerebral cortex, corpus callosum, subventricular zone and external globus pallidus mainly restricted to glial cells. Moreover, continuous administration of the cathepsin X specific inhibitor AMS36 showed protective effects against LPS-induced striatal degeneration, as seen by the decreased extent of striatal lesion and decreased expression of neuroinflammation marker. These results demonstrate that glial upregulated cathepsin X may play a role as a potential pathogenic factor in PD. Inhibition of cathepsin X enzymatic activity thus may be useful in preventing neuroinflammation-induced neurodegeneration.