Atay Vural

Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery

Here we show that ischemia induces sustained contraction of pericytes on microvessels in the intact mouse brain. Pericytes remain contracted despite successful reopening of the middle cerebral artery after 2 h of ischemia. Pericyte contraction causes capillary constriction and obstructs erythrocyte flow. Suppression of oxidative-nitrative stress relieves pericyte contraction, reduces erythrocyte entrapment and restores microvascular patency; hence, tissue survival improves. In contrast, peroxynitrite application causes pericyte contraction. We also show that the microvessel wall is the major source of oxygen and nitrogen radicals causing ischemia and reperfusion–induced microvascular dysfunction. These findings point to a major but previously not recognized pathophysiological mechanism; ischemia and reperfusion-induced injury to pericytes may impair microcirculatory reflow and negatively affect survival by limiting substrate and drug delivery to tissue already under metabolic stress, despite recanalization of an occluded artery. Agents that can restore pericyte dysfunction and microvascular patency may increase the success of thrombolytic and neuroprotective treatments.

A Nanomedicine Transports a Peptide Caspase-3 Inhibitor across the Blood–Brain Barrier and Provides Neuroprotection

Caspases play an important role as mediators of cell death in acute and chronic neurological disorders. Although peptide inhibitors of caspases provide neuroprotection, they have to be administered intracerebroventricularly because they cannot cross the blood–brain barrier (BBB). Herein, we present a nanocarrier system that can transfer chitosan nanospheres loaded with N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone (Z-DEVD-FMK), a relatively specific caspase-3 inhibitor, across BBB. Caspase-3 was chosen as a pharmacological target because of its central role in cell death. Polyethylene glycol-coated nanospheres were conjugated to an anti-mouse transferrin receptor monoclonal antibody (TfRMAb) that selectively recognizes the TfR type 1 on the cerebral vasculature. We demonstrate with intravital microscopy that this nanomedicine is rapidly transported across the BBB without being measurably taken up by liver and spleen. Pre- or post-treatment (2 h) with intravenously injected Z-DEVD-FMK-loaded nanospheres dose dependently decreased the infarct volume, neurological deficit, and ischemia-induced caspase-3 activity in mice subjected to 2 h of MCA occlusion and 24 h of reperfusion, suggesting that they released an amount of peptide sufficient to inhibit caspase activity. Similarly, nanospheres inhibited physiological caspase-3 activity during development in the neonatal mouse cerebellum on postnatal day 17 after closure of the BBB. Neither nanospheres functionalized with TfRMAb but not loaded with Z-DEVD-FMK nor nanospheres lacking TfRMAb but loaded with Z-DEVD-FMK had any effect on either paradigm, suggesting that inhibition of caspase activity and subsequent neuroprotection were due to efficient penetration of the peptide into brain. Thus, chitosan nanospheres open new and exciting opportunities for brain delivery of biologically active peptides that are useful for the treatment of CNS disorders.

The detrimental effect of aging on leptomeningeal collaterals in ischemic stroke.

BACKGROUND Aging is associated with decreased penumbral salvage in patients with ischemic stroke. Another critical factor that determines the fate of penumbra tissue is the degree of collateral circulation, which decreases significantly with aging in experimental models of stroke. In this study, we sought to identify whether these observations could be translated to humans and, therefore, analyzed the effect of patient age on extent of leptomeningeal collaterals in patients with ischemic stroke. METHODS Computed tomography angiography (CTA) source images were used to assess the degree of collateral circulation in a retrospective series of patients with proximal middle cerebral artery (MCA) occlusion. Bivariate and multivariate analyses were used to explore the relationship between patient age and degree of collateral circulation. RESULTS A total of 70 patients were included into the study. Older age (P = .005), history of hypertension (P = .036), higher admission National Institutes of Health Stroke Scale (NIHSS) scores (P = .013), and increased time to CTA (P = .013) were associated with inadequate collaterals in bivariate analyses. In multivariate analysis, older age (P = .008) and higher NIHSS scores (P = .032) remained as the only significant independent variables that were associated with inadequate collaterals. A 10-year increment in patient age increased the odds of inadequate collateral circulation by 1.87 (95% confidence interval: 1.18-2.97). CONCLUSION Our findings show that there is a significant interplay between patient age and adequacy of leptomeningeal collateral circulation in patients with proximal MCA occlusion. The relationship could contribute to adverse tissue outcome and thereby to unfavorable clinical outcome observed in elderly patients with ischemic stroke.

Antiepileptic treatment for anti-NMDA receptor encephalitis: the need for video-EEG monitoring

Anti-NMDA receptor encephalitis is a severe disorder characterised clinically by seizures, autonomic instability, and severe disturbances of memory, behaviour, and cognition. Due to the severity of symptoms, many patients are admitted to the intensive care unit. For some patients, the presence of various movement disorders and abnormal autonomic signs, as well as a history of seizures, lead to a false impression of status epilepticus, which is reported in 6% of the cases. Here, we present two young female patients, one of whom had ovarian teratoma. Both patients were referred to our neurological intensive care unit with a diagnosis of status epilepticus. However, prolonged video-EEG findings were compatible with encephalopathy. We avoided aggressive treatment with intravenous anaesthetics and both patients recovered after immunotherapy, one of whom received surgery. Physicians should be cautious in interpreting abnormal movements and autonomic signs in such patients and video-EEG monitoring is advised when status epilepticus is suspected.

Fulminant Central Plus Peripheral Nervous System Demyelination without Antibodies to Neurofascin.

BACKGROUND Combined central and peripheral nervous system demyelination is a rare and poorly described phenomenon. Recently, anti-neurofascin antibodies were reported to be positive in 86% of these patients in a Japanese cohort. Yet, there seems to be a clinical, radiological, and serological heterogeneity among these patients. In this report, our aim is to describe characteristics of our patients with this entity and compare with others in the literature. METHODS We report clinical, electrophysiological, radiological, and laboratory characteristics of five patients with both multiple sclerosis and chronic inflammatory demyelinating polyradiculoneuropathy from our institutional database containing 1890 MS patients. RESULTS Three patients presented with extensive, active demyelination of both central nervous system and peripheral nervous system with hypertrophic peripheral nerves. Plexuses, trunks, division and cords were involved in the process. Oligoclonal band was negative. Conduction block was not detected. Corticosteroid treatment was not adequate. Others had a slowly progressive clinical course. Serum anti-neurofascin antibody was negative. Review of the literature revealed similar cases with active disease, early-onset hypertrophic peripheral nerves, and central demyelination, in addition to other cases with an insidious course. CONCLUSIONS Patients with combined central and peripheral demyelination form a spectrum. Some patients may have an antibody-mediated syndrome with or without anti-neurofascin antibodies and others seem to represent a coincidence.

The influence of N-desmethylclozapine and clozapine on recognition memory and BDNF expression in hippocampus.

Clozapine, which is the most effective treatment option for treatment-refractory schizophrenia, has been reported to have both positive and negative effects on specific cognitive symptoms in patients with schizophrenia and in animal models of cognition. Clozapine has a major metabolite, N-desmethylclozapine (NDMC), which has been suggested to be more effective than clozapine itself to improve cognition. Enhancement of brain derived neurotrophic factor (BDNF) expression in the hippocampus has been proposed to contribute to the cognitive-enhancing effects of antipsychotic drugs. The aims of this study were to investigate the change in short and long term memory as assessed by the novel object recognition (NOR) test and BDNF expression in hippocampus produced by an acute hypoglutamatergic model of memory impairment in schizophrenia induced by administration of the NMDA receptor non-competitive antagonist, MK-801 and the ability of clozapine and NDMC to prevent the deleterious effects of MK-801. Both short (1 h) and long-term (24 h) memory were impaired in MK-801 (0.1 mg/kg) - and clozapine (5 mg/kg)-, but not NDMC (5 mg/kg)-treated rats. Neither NDMC (5 mg/kg) nor clozapine (5 mg/kg) reversed the effect of MK-801. Western blotting studies showed that BDNF levels in hippocampus were not different in rats administered MK-801 alone, clozapine or NDMC alone. These results show that in this model clozapine affects memory negatively, while NDMC does not. The absence of impairment of NOR with NDMC is consistent with previous evidence that it has a more benign effect on cognition than does the parent compound, and may support the efforts to study its effects on other cognitive functions. These findings do not provide any support for the role of BDNF in the MK-801-induced impairment in NOR or for differences between clozapine and NDMC.

Brachial Diparesis due to Motor Neuronopathy as One of the Predominant Presenting Signs of Occult Small Cell Lung Carcinoma

Sensory neuronopathy is a well-established presentation in paraneoplastic neurological syndromes that is mostly associated with small cell lung cancer and anti-Hu antibodies. Motor neuronopathy, on the other hand, is an extremely rare observation in this syndrome. A 56-year-old man presented with asymmetric brachial diparesis and sensory ataxia. Electrophysiological studies revealed sensory ganglionopathy and progressive anterior horn degeneration in cervical segments. Small cell lung carcinoma with associated anti-Hu antibodies was later diagnosed. The patient did not improve despite the administration of steroids and chemotherapy. Paraneoplastic syndromes may exceptionally present with a bilateral arm weakness. Cases accompanied by sensory ganglionopathy should therefore be promptly investigated for any underlying malignancy.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) in Two Siblings with Neuropsychiatric Symptoms

erebral autosomal dominant arteriopathy with subcorti-cal infarcts and leukoencephalopathy (CADASIL) is arare hereditary disease that presents with various neurologicaland/or psychiatric symptoms, such as stroke, migraine with aura,cognitive changes, mood disorders, and dementia. Mutations inthe Notch3 gene have been documented in most of the patients.Clinically, the most useful diagnostic tool is cranial magneticresonance (MR) imaging, which demonstrates widespread sub-cortical leukoencephalopathy associated with hyperintensities inbasal ganglia, thalamus, and brainstem. Psychiatric symptomsare seen in 20%–41% of the patients, and are rarely the initialpresenting symptom. Here we present two siblings in their 40swith prominent psychiatric complaints. Clinical diagnosis ofCADASIL was made years later, after a careful personal andfamily history combined with typical MR imaging findings.Both patients had a missense mutation in exon 4 of Notch3. Ifpatients with various psychiatric symptoms have a history ofheadache, stroke-like episodes, or cognitive changes, and a pos-itive family history of similar complaints, they should undergocranial MR imaging. In case the imaging demonstrates unex-plained leukoencephalopathy, patients should be investigated forCADASIL.Cerebral autosomal dominant arteriopathy with subcor-tical infarcts and leukoencephalopathy (CADASIL) is a rarehereditary brain disease that in most patients occurs due tomutations of the notch 3 gene on chromosome 19q12.

Bright and dark vessels on stroke imaging: different sides of the same coin?

PURPOSE Prominent hypointense cerebral vessels on susceptibility-weighted imaging (SWI) and the hyperintense vessel sign (HVS) on fluid-attenuated inversion recovery (FLAIR) imaging are considered as markers of compromised tissue perfusion in cerebral ischemia. In this study, we aimed to identify the correlation between HVS on FLAIR and hypointense vessels on SWI, and to determine whether these imaging features provide independent prognostic information in patients with ischemic stroke. METHODS We retrospectively analyzed consecutive ischemic stroke patients with proximal middle cerebral artery (MCA) occlusion who underwent SWI and FLAIR within 24 h of symptom onset. The presence of hypointense vessels on SWI and hyperintense vessels on FLAIR in >4 of 10 slices encompassing the MCA territory were considered to represent prominent hypoperfusion. RESULTS Among 50 patients, 62% had a prominent HVS on FLAIR and 68% had prominent hypointense vessels on SWI. There was a moderate but significant correlation between the number of slices with HVS on FLAIR and prominent hypointense vessels on SWI (r=0.425, P = 0.002). In multivariate analyses, the prominence of hypointense vessels on SWI, but not HVS on FLAIR, was significantly associated with a higher discharge NIHSS score (P = 0.027), mRS score (P = 0.021), and lesion growth (P = 0.050). CONCLUSION The significant, albeit moderate, correlation between markers of compromised tissue perfusion on FLAIR and SWI suggests that these imaging features reflect different but interrelated aspects of cerebral hemodynamics during ischemic stroke. Our findings highlight that while HVS on FLAIR denotes the presence of leptomeningeal collaterals, hypointense vessels on SWI signify the sufficiency of cerebral blood flow at the tissue level and are therefore more critical in terms of prognosis.

Poloxamer-188 and citicoline provide neuronal membrane integrity and protect membrane stability in cortical spreading depression

Under pathological conditions such as brain trauma, subarachnoid hemorrhage and stroke, cortical spreading depression (CSD) or peri-infarct depolarizations contribute to brain damage in animal models of neurological disorders as well as in human neurological diseases. CSD causes transient megachannel opening on the neuronal membrane, which may compromise neuronal survival under pathological conditions. Poloxamer-188 (P-188) and citicoline are neuroprotectants with membrane sealing properties. The aim of this study is to investigate the effect of P-188 and citicoline on the neuronal megachannel opening induced by CSD in the mouse brain. We have monitored megachannel opening with propidium iodide, a membrane impermeable fluorescent dye and, demonstrate that P-188 and citicoline strikingly decreased CSD-induced neuronal PI influx in cortex and hippocampal dentate gyrus. Therefore, these agents may be providing neuroprotection by blocking megachannel opening, which may be related to their membrane sealing action and warrant further investigation for treatment of traumatic brain injury and ischemic stroke.