Search

Background: Cognitive impairment (CI) is detected in 40-70% of multiple sclerosis (MS) patients, but only 33-50% of the CI variance is explained by the disease burden assessed by MRI. The cognitive reserve (CR) hypothesis has been postulated to account for this discrepancy. So far, most previous studies have confirmed the CR hypothesis in MS but failed to examine CR indices collectively or use clinically relevant neuropsychological assessments. The aim of this study was to replicate previous findings for the effect of CR (and its counterpart; brain reserve-BR) in MS by considering these caveats., Methods: 128 RRMS and 13 SPMS patients were recruited in this cross-sectional study (mean age 43.5 ± 10.4 years old, 73% females, mean disease duration 153.7 ± 89.4). CR was assessed by the Cognitive Reserve Index questionnaire (CRIq) and BR by the intracranial volume. Neuropsychological assessment was made by using the recommended for clinicians Brief International Cognitive Assessment for MS (BICAMS) tool. Other measurements included clinical characteristics, psychological status, fatigue, and MRI volumetric imaging parameters. Multiple linear regression models were implemented to ascertain the putative moderating role (i.e. interaction terms) of CR and BR in cognition., Results: Exploratory univariate analyses revealed significant negative correlations between both disability and depression with cognitive scores (rho = -0.382, p < 0.001, rho = -0.278, p = 0.001, respectively), only. After controlling for gender, disability and depression, a significant moderating protective effect of CR on the associations between both grey and peripheral grey matter volumes with verbal memory was found (beta = 1.834, p = 0.045, beta = 1.936, p = 0.04 for the interaction terms, respectively). Also, BR moderated the effect of the total brain volume on verbal memory (beta = 1.516, p = 0.043)., Conclusion: This study showed that by using composite measures of CR and simple, clinically-orientated neuropsychological assessments, the protective role of CR and BR is mostly restricted to memory function. Future research should embark on investigating interventions that will aim to enhance CR for the prevention of CI in MS., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Activity-dependent neuroprotective protein (ADNP), essential for brain formation, was discovered as a leading de novo mutated gene causing the autism-like ADNP syndrome. This syndrome is phenotypically characterized by global developmental delays, intellectual disabilities, speech impediments, and motor dysfunctions. The Adnp haploinsufficient mouse mimics the human ADNP syndrome in terms of synapse density and gene expression patterns, as well as in developmental, motor, and cognitive abilities. Peripheral ADNP was also discovered as a biomarker for Alzheimer's disease and schizophrenia, with nasal administration of the ADNP snippet peptide NAP (enhancing endogenous ADNP activity) leading to partial cognitive and functional protection at the cellular, animal and clinical settings. Here, a novel formulation for effective delivery of NAP is provided with superior brain penetration capabilities. Also provided are methods for treating pertinent clinical implications such as autism, cognitive impairments, olfactory deficits, and muscle strength using the formulation in the Adnp haploinsufficient mouse. Results showed a dramatically specific increase in brain/body bioavailability with the new formulation, without breaching the blood brain barrier. Additional findings included improvements using daily intranasal treatments with NAP, at the behavioral and brain structural levels, diffusion tensor imaging (DTI), translatable to clinical practice. Significant effects on hippocampal and cerebral cortical expression of the presynaptic Slc17a7 gene encoding vesicular excitatory glutamate transporter 1 (VGLUT1) were observed at the RNA and immunohistochemical levels, explaining the DTI results. These findings tie for the first time a reduction in presynaptic glutamatergic synapses with the autism/Alzheimer's/schizophrenia-linked ADNP deficiency coupled with amelioration by NAP (CP201).

Myotonic dystrophy type 2(DM2), inherited in an autosomal, dominant manner, is clinically characterized by muscle weakness, variable myotonia, cataract and multiorgan involvement, including the Central Nervous System. Recent data from literature indicate a possible autoimmune susceptibility of patients with DM2, while white matter abnormalities are a common feature of the disease. We report herein the case of a 38-year old woman, with the rare co-existence of DM2 and MS and argue about the challenging differential diagnosis if CNS involvement is present in DM2 patients. Thus, is it another expression of a multisystem disorder or an unfortunate pure coincidence?, (Copyright © 2018 Elsevier B.V. All rights reserved.)

Type 2 diabetes and hypertension are associated with cognitive dysfunction that includes pathological changes in brain tissue. It was speculated that the beneficial hypotensive effect of telmisartan, an angiotensin receptor 1 blocker, and its unique hypoglycemic effect due to its PPARγ-activation, could ameliorate the ​ pathological changes in the brain​ that accompany​ these diseases. We examined the effect of telmisartan on brain changes in magnetic resonance imaging (MRI) T2-weighted scans, and behavioral and histological findings in the Cohen-Rosenthal Diabetic Hypertensive (CRDH) rat. Baseline and post-treatment values with telmisartan/vehicle (3 months) of blood pressure, blood glucose levels, behavioral tests, brain MRI scanning and immunohistological staining were obtained. Telmisartan significantly lowered blood pressure and blood glucose levels; induced consistent T2 reduction in specific gray and white regions including hippocampus, corpus callosum, amygdala and cortical regions; and significantly improved performance on behavioral tasks. Immunohistological analysis of the brain revealed significant amelioration of diabetes/hypertension-induced changes in white matter regions and microglia, evidenced by preserved myelin (LBF marker), and improved microglial neuronal markers GFAP, GAP43 and Iba1 expression. In conclusion, the behavioral performance, longitudinal MRI study and histology staining revealed the protective effects of telmisartan on brain microstructure and cognitive function., (Copyright © 2016. Published by Elsevier B.V.)

Postnatally isolated neural precursor cells (piNPCs) from mouse cerebral tissue have been studied in cell-based therapeutic approaches for Experimental Autoimmune Encephalomyelitis (EAE). Transplantation experiments in EAE rodents revealed that piNPCs manage to integrate into the host tissue and ameliorate clinical symptoms. When cultured in vitro, mouse cerebral piNPCs form neurospheres consisting of immature cells positive for polysialylated neural adhesion molecule (PSA-NCAM) that differentiate mainly towards glial cells, but also neurons. Herein, we have characterized piNPCs immunophenotype, with flow cytometry. NPCs were positive for CD24, CD44, and CD133 though negative for CD15, CD184 and CD49d. This immunophenotype, determined for the first time, among cells isolated from neonates might be useful for the identification of NPC population aiming at the development of transplantation protocols., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Exogenous transplanted neural precursor cells (NPCs) exhibit miscellaneous immune-modulatory effects in models of autoimmune demyelination. However, the regional interactions of NPCs with the host brain tissue in remissive inflammatory events have not been adequately studied. In this study we used the chronic MOG-induced Experimental Autoimmune Encephalomyelitis (EAE) model in C57BL/six mice. Based on previous data, we focused on neuropathology at Day 50 post-induction (D50) and studied the expression of connexin43 (Cx43) and Cx47, two of the main glial gap junction (GJ) proteins, in relation to the intraventricular transplantation of GFP(+) NPCs and their integration with the host tissue. By D50, NPCs had migrated intraparenchymally and were found in the corpus callosum at the level of the lateral ventricles and hippocampus. The majority of GFP(+) cells differentiated with simple or ramified processes expressing mainly markers of mature GLIA (GFAP and NogoA) and significantly less of precursor glial cells. GFP(+) NPCs expressed connexins and formed GJs around the hippocampus more than lateral ventricles. The presence of NPCs did not alter the increase in Cx43 GJ plaques at D50 EAE, but prevented the reduction of oligodendrocytic Cx47, increased the number of oligodendrocytes, local Cx47 levels and Cx47 GJ plaques per cell. These findings suggest that transplanted NPCs may have multiple effects in demyelinating pathology, including differentiation and direct integration into the panglial syncytium, as well as amelioration of oligodendrocyte GJ loss, increasing the supply of potent myelinating cells to the demyelinated tissue., (© 2015 Wiley Periodicals, Inc.)

Background: The aim of the present meta-analysis was to evaluate the effect of disease-modifying drugs (DMD) on brain atrophy in patients with relapsing-remitting multiple sclerosis (RRMS) using available randomized-controlled trial (RCT) data., Methods: We conducted a systematic review and meta-analysis according to PRISMA guidelines of all available RCTs of patients with RRMS that reported data on brain volume measurements during the study period., Results: We identified 4 eligible studies, including a total of 1819 RRMS patients (71% women, mean age 36.5 years, mean baseline EDSS-score: 2.4). The mean percentage change in brain volume was found to be significantly lower in DMD versus placebo subgroup (standardized mean difference: -0.19; 95%CI: -0.27--0.11; p<0.001). We detected no evidence of heterogeneity between estimates (I2 = 30%, p = 0.19) nor publication bias in the Funnel plots. Sensitivity analyses stratifying studies according to brain atrophy neuroimaging protocol disclosed no evidence of heterogeneity (p = 0.16). In meta-regression analyses, the percentage change in brain volume was found to be inversely related with duration of observation period in both DMD (meta-regression slope = -0.03; 95% CI: -0.04--0.02; p<0.001) and placebo subgroups (meta-regression slope = -0.05; 95% CI: -0.06--0.04; p<0.001). However, the rate of percentage brain volume loss over time was greater in placebo than in DMD subgroup (p = 0.017, ANCOVA)., Conclusions: DMD appear to be effective in attenuating brain atrophy in comparison to placebo and their benefit in delaying the rate of brain volume loss increases linearly with longer treatment duration.

Multiple sclerosis (MS) is a chronic disease with an inflammatory and neurodegenerative pathology. Axonal loss and neurodegeneration occurs early in the disease course and may lead to irreversible neurological impairment. Changes in brain volume, observed from the earliest stage of MS and proceeding throughout the disease course, may be an accurate measure of neurodegeneration and tissue damage. There are a number of magnetic resonance imaging-based methods for determining global or regional brain volume, including cross-sectional (e.g. brain parenchymal fraction) and longitudinal techniques (e.g. SIENA [Structural Image Evaluation using Normalization of Atrophy]). Although these methods are sensitive and reproducible, caution must be exercised when interpreting brain volume data, as numerous factors (e.g. pseudoatrophy) may have a confounding effect on measurements, especially in a disease with complex pathological substrates such as MS. Brain volume loss has been correlated with disability progression and cognitive impairment in MS, with the loss of grey matter volume more closely correlated with clinical measures than loss of white matter volume. Preventing brain volume loss may therefore have important clinical implications affecting treatment decisions, with several clinical trials now demonstrating an effect of disease-modifying treatments (DMTs) on reducing brain volume loss. In clinical practice, it may therefore be important to consider the potential impact of a therapy on reducing the rate of brain volume loss. This article reviews the measurement of brain volume in clinical trials and practice, the effect of DMTs on brain volume change across trials and the clinical relevance of brain volume loss in MS.

Epidemiological studies show that stimulating activities reduce the risk of dementia. In animal models of Alzheimer disease, there have been conflicting results of the effects of environmental enrichment (EE) on disease-related amyloid pathology. Here, we tested the direct effect of EE, independently of amyloid pathology, on brain neurofibrillary tangles (NFTs), which best correlate with dementia. We exposed transgenic mice (E257K/P301S-Tau-Tg driven by the natural tau promoter) to moderate nonstrained EE or regular environment. Concomitant with neurogenesis, we detected a decrease in NFT burden and a decrease in the activation of microglia in EE versus regular-environment mice. There was also a trend toward improvement in cognitive tasks in the EE mice. Increased immunoreactivity of brain-derived neurotrophic factor, which is involved in the regulation of tau phosphorylation, was detected in the EE mice, suggesting its possible involvement in the beneficial effects on NFTs and other parameters in the EE mice. These results suggest that NFTs may be directly responsive to environmental stimulating activities and that even nonstrained activities may mitigate tauopathies independent of the involvement of amyloid.

Background and Purpose: Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT(1A) , on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide., Experimental Approach: Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure., Key Results: Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment., Conclusions and Implications: Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

Recent studies on neural precursor cell (NPC) transplantation in multiple sclerosis animal models reveal that these cells exert their therapeutic effect mainly because of immunomodulation rather than cell replacement. In this study intraventricularly transplanted NPCs in mice, induced experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis, improved the clinical symptoms and suppressed inflammation in the brain by enhancing the apoptosis of inflammatory cells. However, the same treatment failed to reduce significantly the inflammatory cells in the spinal cord, the pathology of which predominantly determines the clinical manifestation of experimental autoimmune encephalomyelitis. Our findings suggest that immunosuppression is rather a local phenomenon and thus, bystander neuroprotective mechanisms triggered by NPC intraventricular transplantation should be accountable for their therapeutic effect.

In multiple sclerosis lesions resident oligodendrocyte progenitor cells (OPCs) are present, but fail to remyelinate. In the current study we examined whether neural precursor cell (NPC) transplantation can facilitate host brain-derived remyelination. We used the chronic cuprizone-induced demyelination model in aged mice, in which slow remyelination follows cuprizone removal. NPCs were transplanted to the lateral ventricles (intracerebroventricular) of cuprizone-induced demyelinated brains. In this experimental setup, transplanted cells remained mostly in the periventricular area in an undifferentiated state. The extent of demyelination, remyelination, and proliferation of host brain regenerative cell population were examined at 1 week posttransplantation in the splenium of the corpus callosum, which was devoid of any transplanted cells. Transplantation of NPCs, but not of control, human embryonic kidney cells, significantly enhanced remyelination compared with sham-operated mice. Remyelination was performed exclusively by host brain OPCs. The proregenerative effect of transplanted NPCs was related to an increase in the proliferation of host brain OPCs. To examine the mechanism that underlies the proregenerative effect of NPCs in vitro, we used an NPC-OPC coculture system. These experiments indicated that NPCs induced the proliferation of OPCs and facilitated their differentiation into mature oligodendrocytes. The mitogenic effect of NPCs was mediated by platelet-derived growth factor-AA and fibroblast growth factor-2. In conclusion, NPC transplantation enhances host-derived myelin regeneration following chronic demyelination. This trophic effect may stimulate resident OPCs to overcome the remyelination failure in multiple sclerosis.

The human central nervous system (CNS) is targeted by different pathogens which, apart from pathogens' intranasal inoculation or trafficking into the brain through infected blood cells, may use a distinct pathway to bypass the blood-brain barrier by using the gastrointestinal tract (GIT) retrograde axonal transport through sensory or motor fibres. The recent findings regarding the enteric nervous system (often called the "little brain") similarities with CNS and GIT axonal transport of infections resulting in CNS neuroinflammation are mainly reviewed in this article. We herein propose that the GIT is the vulnerable area through which pathogens (such as Helicobacter pylori) may influence the brain and induce multiple sclerosis pathologies, mainly via the fast axonal transport by the afferent neurones connecting the GIT to brain.

Background and Purpose: Hepatic encephalopathy is a neuropsychiatric syndrome caused by liver failure. In view of the effects of cannabinoids in a thioacetamide-induced model of hepatic encephalopathy and liver disease and the beneficial effect of capsaicin (a TRPV1 agonist) in liver disease, we assumed that capsaicin may also affect hepatic encephalopathy., Experimental Approach: Fulminant hepatic failure was induced in mice by thioacetamide and 24 h later, the animals were injected with one of the following compound(s): 2-arachidonoylglycerol (CB(1), CB(2) and TRPV1 receptor agonist); HU308 (CB(2) receptor agonist), SR141716A (CB(1) receptor antagonist); SR141716A+2-arachidonoylglycerol; SR144528 (CB(2) receptor antagonist); capsaicin; and capsazepine (TRPV1 receptor agonist and antagonist respectively). Their neurological effects were evaluated on the basis of activity in the open field, cognitive function in an eight-arm maze and a neurological severity score. The mice were killed 3 or 14 days after thioacetamide administration. 2-arachidonoylglycerol and 5-hydroxytryptamine (5-HT) levels were determined by gas chromatography-mass spectrometry and high-performance liquid chromatography with electrochemical detection, respectively., Results: Capsaicin had a neuroprotective effect in this animal model as shown by the neurological score, activity and cognitive function. The effect of capsaicin was blocked by capsazepine. Thioacetamide induced astrogliosis in the hippocampus and the cerebellum and raised brain 5-hydroxytryptamine levels, which were decreased by capsaicin, SR141716A and HU-308. Thioacetamide lowered brain 2-arachidonoylglycerol levels, an effect reversed by capsaicin., Conclusions: Capsaicin improved both liver and brain dysfunction caused by thioacetamide, suggesting that both the endocannabinoid and the vanilloid systems play important roles in hepatic encephalopathy. Modulation of these systems may have therapeutic value.

Statin treatment has been associated with a reduced risk of Alzheimer disease and decreased amyloid deposition in mouse models. No animal studies have reported effects of statins on tau aggregates and neurofibrillary tangles (NFTs), the pathological hallmarks of Alzheimer disease that correlate with dementia. We investigated the effect of statins on NFTs in a transgenic mouse tauopathy model and found the following: 1) 1-month treatment with the blood-brain barrier-permeable agent simvastatin in normocholesterolemic aged mice significantly reduced the NFT burden and decreased lectin-positive microglia; 2) simvastatin significantly decreased NFTs and improved T-maze performance in young animals treated for 8 months; 3) treatment of hypercholesterolemic mice for 5 months with blood-brain barrier-impermeable atorvastatin markedly reduced the NFT burden and decreased lectin-positive microglia; 4) nonstatin cholesterol-lowering strategies showed a modest NFT decrease compared with statin treatment; and 5) there was a positive correlation between microglial and NFT burden (r = 0.8). Together, these results suggest that statins reduce NFT burden irrespective of blood-brain barrier permeability at both early and late ages in long- and short-term treatment paradigms and under normocholesterolemic and hypercholesterolemic conditions. The decrease in microglia, coupled with the limited effect of nonstatin cholesterol lowering, suggests that the anti-NFT effect of statins may be related to their anti-inflammatory and not necessarily to their cholesterol-lowering properties. Statins may provide therapy against NFTs in tauopathies, particularly when NFTs are the major neuropathologic component.

The neurofibrillary-tangles (NTFs), characteristic of tauopathies including Alzheimer's-disease (AD), are the pathological features which correlate best with dementia. The objective of our study was to generate an authentic transgenic (tg) animal model for NFT pathology in tauopathy/AD. Previous NFT-tg mice were driven by non-related/non-homologous promoters. Our strategy was to use the natural tau promoter for expressing the human-tau (htau) gene with two mutations K257T/P301S (double mutant, DM) associated with severe phenotypes of frontotemporal-dementia in humans. Cellular, biochemical, behavioral and electrophysiological studies were subsequently conducted. The tg mice showed a tolerated physiological level of the DM-htau protein, mostly in cortex and hippocampus. The mice demonstrated tauopathy-like characteristics, which increased with age, that included NFT-related pathology, astrogliosis, argyrophilic plaque-like (amyloid-free) structures in brain, with memory deficits and signs of anxiety. Moreover, the tg mice showed a robust synaptic plasticity deficit selectively expressed in a severe impairment in their ability to maintain hippocampal long-term-potentiation (LTP) in response to stimulation of the perforant path, providing evidence that "tau-pathology only" is sufficient to cause this memory and learning-associated deficit. This is a unique mutant-htau-tg model which presents a wide spectrum of features characteristic of tauopathy/AD, which does not show unrelated motor deficits described in other models of tauopathy. In addition, expressing the DM-htau in a neuronal cell model resulted in tau-aggregation, as well as impaired microtubule arrangement. Both animal and cell models, which were regulated under the natural tau promoter (of rat origin), provide authentic and reliable models for tauopathy, and offer valuable tools for understanding the molecular events underlying tauopathies including AD.

PrP(C), the cellular isoform of prion protein, is widely expressed in most tissues, including brain, muscle and gastrointestinal tract. Despite its involvement in several bioprocesses, PrP has still no apparent physiological role. During propagation of transmissible spongiform encephalopathies (TSE), prion protein is converted to the pathological isoform, PrP(Sc), in a process believed to be mediated by unknown host factors. The identification of proteins associated with PrP may provide information about both the biology of prions and the pathogenesis of TSE. Thus far, PrP(C) has been shown to interact with synaptic proteins, components of the cytoskeleton and intracellular proteins involved in signalling pathways. Here, we describe the association of PrP with the beta4 subunit of nicotinic acetylcholine receptor (nAChR), as indicated by co-immunoprecipitation assays and double-label immunofluorescence. The interaction between prion protein and native beta4 subunit was further studied by affinity chromatography, using immobilized and refolded recombinant PrP as a bait and brain homogenates from normal individuals. Additionally, the participation of beta4 subunit in the pathogenesis of TSE was studied by in vivo assays. beta4(-/-) and wild-type mice were challenged with the RML (Rocky Mountain Laboratories) infectious agent. Transgenic animals displayed altered incubation times but the deletion of beta4 subunit did not result in a significant change of the incubation period of the disease. Our results suggest that PrP(C) is a member of a multiprotein membrane complex participating in the formation and function of alpha3beta4 nAChR.

Background: A possible role of autoimmunity in Alzheimer disease pathogenesis has recently attracted increasing attention. Vaccination with amyloid-beta peptide was reported to cause marked reduction in amyloid deposition, but it also induced encephalitis. Not much is known regarding neurofibrillary tangle-related autoimmune effects., Objective: To use the main component of tangles-microtubule-associated tau protein-to test the feasibility of active induction of a neuroautoimmune disorder in mice., Design: Prospective, randomized controlled animal study., Setting: University medical center research laboratory. Subjects Female C57BL/6 mice., Interventions: Inoculation with recombinant human tau protein emulsified in complete Freund adjuvant and with pertussis toxin., Main Outcome Measures: Clinical, immunologic, pathologic, and behavioral evaluations were performed., Results: Vaccination with tau protein induced histopathologic features of Alzheimer disease and tauopathies, indicated by the presence of neurofibrillary tangle-like structures, axonal damage, and gliosis. Also, mononuclear infiltrates without demyelination in the central nervous system, accompanied by neurologic deficits (such as a limp tail and limb paralysis), were observed. Anti-tau antibodies were detected in the serum of tau-immunized mice., Conclusions: These results provide a link between tau autoimmunity and tauopathy-like abnormalities and indicate potential dangers of using tau for immunotherapy. This experimental autoimmune tauopathy-like model is due to a pathogenic immune response against an intraneuronal antigen and is not related to myelin antigens.

Prion propagation involves conversion of host PrP(C) to a disease-related isoform, PrP(Sc), which accumulates during disease and is the principal component of the transmissible agent. Proteolysis seems to play an important role in PrP metabolism. Plasminogen, a serine protease precursor, has been shown to interact with PrP(Sc). Plasminogen can be proteolytically activated by tissue plasminogen activator (tPA). Recent reports imply a crosstalk between tPA-mediated plasmin activation and PrP. In our study, both tPA activity and tPA gene expression were found elevated in TSE-infected brains as compared to their normal counterparts. Furthermore, it was proved that PrP(Sc), in contrast to PrP(C), could not be degraded by plasmin. In addition, it was observed that TSE symptoms and subsequent death of plasminogen-deficient and tPA-deficient scrapie challenged mice preceded that of wild-type controls. Our data imply that enhanced tPA activity observed in prion infected brains may reflect a neuro-protective response.

Results from several laboratories indicate that apoptosis via the P53 pathway is involved in prion disease pathogenesis. Prion diseases, among them scrapie and BSE, are a group of fatal neurodegenerative disorders associated with the conversion of PrP(C) to PrP(Sc), its conformational abnormal isoform. In this work, we tested whether an established anti-apoptotic reagent, PFT, which has been shown in different systems to inhibit P53 activity, can delay the outbreak of prion disease in infected animals. Our findings indicate that although PFT efficiently reduced caspase 3 expression in brains from scrapie sick hamsters, as well as inhibited PrP(Sc) accumulation in cell culture, it had no effect on disease incubation time or PrP(Sc) accumulation in vivo. We conclude that the P53 dependent apoptosis may not be an obligatory mechanism for prion disease-induced cell death.

Multiple sclerosis is no longer considered to simply be an autoimmune demyelinating disease. Axonal destruction is another central pathological feature and a contributor to the accumulating disability of disease progression. The mechanism underlying axonal pathology has not been fully clarified but does not appear to be a simple one. The relationship between axonal damage and other components of the pathological features such as demyelination, inflammation and remyelination are under intense investigation. Experimental data suggest that therapeutic interventions such as the induction of rapid remyelination may lead to the protection of axons. In addition to immunomodulation, future strategies for neuroprotection may be of great importance.

Background and Purpose: We sought to determine the cerebroprotective potential of NAP, a synthetic octapeptide related to vasoactive intestinal peptide. Activity-dependent neuroprotective protein mediates some of the protective effects of vasoactive intestinal peptide. The neuroprotective NAP sequence is derived from activity-dependent neuroprotective protein., Methods: Spontaneously hypertensive rats underwent permanent middle cerebral artery occlusion by craniotomy and electrocoagulation. After dose-response and time-course experiments, the animals were injected with NAP (3 microg/kg) or vehicle intravenously 1 hour after stroke onset. Another group of rats was injected with the D-amino acid isomer of NAP (D-NAP) and served as a negative control. Rats were examined for motor and behavioral deficits 24 hours to 30 days later, and infarct volumes were determined. The effect of NAP administration on apoptotic death was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and caspase-3 stainings., Results: NAP significantly reduced motor disability and infarct volumes compared with vehicle or D-NAP when tested at 24 hours after stroke onset (9.67+/-1.4% versus 17.04+/-1.18% and 19.19+/-1.9% of hemispheric volume, respectively; P<0.05). NAP given 4 but not 6 hours after permanent middle cerebral artery occlusion still conferred significant neuroprotection (infarct volume 10.9+/-3.9% of hemispheric volume; P<0.05 versus vehicle). Long-term studies demonstrated that infarct volumes and disability scores remained significantly lower after 30 days in NAP-treated animals. NAP significantly reduced the number of apoptotic cells., Conclusions: Our results indicate that the durable cerebroprotection by NAP involves antiapoptotic mechanisms.