Carolina Sampedro

Cerebrolysin® reduces microglial activation in vivo and in vitro: a potential mechanism of neuroprotection

Neurotrophins, such as NGF, BDNF and NT-3 play a regulatory role on the function of microglial cells in vivo and in vitro, and the identification of new compounds with neurotrophic properties is becoming a new strategy for the prevention and/or treatment of neurodegenerative disorders. In this study we describe the use of two different models to demonstrate the ability of Cerebrolysin to reduce microglial activation. The results of these in vitro and in vivo studies indicate that Cerebrolysin might exert a neuroimmunotrophic activity reducing the extent of inflammation and accelerated neuronal death under pathological conditions such as those observed in neurodegenerative diseases.

Oral Cerebrolysin® enhances brain alpha activity and improves cognitive performance in elderly control subjects

Cerebrolysin is a porcine brain derived peptide preparation with potential neurotrophic activity. The effects of a single oral dose of the Cerebrolysin solution (30 ml) on brain bioelectrical activity and on cognitive performance were investigated in healthy elderly people. A single oral dose of Cerebrolysin induced a progressive increase in relative alpha activity power from 1 to 6 hours after treatment in almost all the brain electrodes in elderly control subjects. As compared with baseline alpha power (45.8+/-9.5%), the increase in relative alpha activity in the left occipital electrode (O1) reached significant values at 1 hour (57.2+/-8.5%; p < 0.05), 3 hours (59.4+/-7.6%; p < 0.05) and 6 hours (63.4+/-9.8%; p < 0.05) after Cerebrolysin administration. Enhancement in relative alpha power was accompanied by a generalized decrease in slow delta activity that was maximum at 6 hours after Cerebrolysin intake. A significant improvement in memory performance, evaluated with items of the ADAS cog, was also found in elderly people taken a single dose of oral Cerebrolysin (6.9+/-1.0 errors at baseline versus 4.9+/-1.0 errors after treatment; p < 0.01). This memory improvement was more evident in recognition (2.8+/-0.6 errors vs. 1.5+/-0.7 errors; p < 0.05) than in recall tasks (4.1+/-0.5 errors versus 3.4+/-0.5 errors; ns). These data indicate that Cerebrolysin potentiates brain alpha activity, reduces slow EEG delta frequencies and improves memory performance in healthy elderly humans, suggesting that this compound activates cerebral mechanisms related to attention and memory processes. According to the present results, it seems that oral Cerebrolysin might be useful for the treatment of memory impairment and brain damage in eldely subjects with or without neurodegenerative disorders.

Reduced TNF-α and increased IGF-I levels in the serum of Alzheimer's disease patients treated with the neurotrophic agent cerebrolysin.

According to current scientific knowledge, excess tumour necrosis factor-α (TNF-α) and low insulin-like growth factor-I (IGF-I) are pathogenic-risk factors that constitute therapeutic targets for Alzheimers disease (AD). Changes in serum TNF-α, total and dissociable IGF-I levels were determined by ELISA in 207 AD patients completing a 24-wk, double-blind, placebo-controlled trial to evaluate the effects of the neurotrophic compound Cerebrolysin (Cere: 10, 30 or 60 ml for 12 wk). At week 24, Cere reduced TNF-α and enhanced dissociable IGF-I with respect to placebo in a dose-related manner. TNF-α decreased in parallel with behavioural disturbances. Increases in total IGF-I were induced by 60 ml Cere and correlated significantly with improvements in global function, disabilities and behaviour in late-onset AD patients. These results showing for the first time the opposite influence of one anti-dementia treatment on serum TNF-α and IGF-I suggest the contribution of both factors to the clinical effects of Cere, and probably other drugs.

Short term food supplementation effects of a fish derived extract on the immunological status of pregnant rats and their sucking pups

There is emerging evidence that PUFAs influence immune functions by controlling the normal inflammatory process and may do so by serving as a signal modulator that regulates specific enzymatic activities typically elevated during inflammation at the inflammation site. In the present study, the effect of 12 weeks food supplementation with E-SAR 94010, a marine fish extract, before and during pregnancy and lactation in Sprague-Dawley rats and their offspring was investigated. Triglyceride plasma levels of pups and their mothers was lower in the treated groups than in the control group. No significant differences in the atherogenic index (total cholesterol-HDLcholesterol/HDLcholesterol) were observed. Studies on the lymphocyte cell marker suggest a clear immune activation as measured by the increased levels of CD25, CD28, CD54, CD62 and CD56 on lymphocytes derived from both E-SAR treated mothers and newborns. Therefore the present results indicate that E-SAR-94010 dietary supplementation can be responsible for an increased level of immune surveillance.

Neuroprotective Effect of Atremorine in an Experimental Model of Parkinson’s Disease

Parkinsonian-like state was generated in mice by the administration of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) to study the effects of Atremorine in Parkinsons disease (PD) related neuropathology and behavior deficits. This devastating disease is caused by the progressive degeneration of dopaminergic neurons in the substantia nigra. Numerous therapeutic strategies have been developed to protect neuronal damage, although no effective treatment for PD has been validated yet. This study tested the preventive and therapeutic neuroprotective effect of Atremorine on MPTP parkinsonian mouse model. In addition to behavioral analysis, nigrostriatal dopaminergic neurons and inflammation biomarkers were directly quantified in the affected brain regions by specific antibody-antigen-binding methods. The affected neuronal populations and behavioural alterations induced by MPTP were significantly impaired in mice when treated with Atremorine-rich diet. Differences in the Atremorine content in diet induced some degrees of neuropathological and behavior therapeutical improvement, based on the progressive beneficial effects observed in nigro-striatal dopaminergic neurons of MPTPinduced mice. Data demonstrated that Atremorine promotes neuroprotection and behavior recovery in the injured MTPT-mouse brain by modulating the expression levels of tyrosine hydroxylase, glial proteins, apoptosis and endogenous dopamine and neuromelanin concentrations, probably the key to recover the basal ganglia function.

Dopaminergic Neuroprotection with Atremorine in Parkinson's disease

Patients with Parkinsons disease (PD) are looking forward to new therapeutic strategies that may gradually decelerate the rate of neurodegenerative decline, associated with mobility restrictions and related morbidity. Its continuous neurodegenerative process, exacerbated by genetic mutations or environmental toxins, involves a progressive reduction in the dopamine neurotransmission levels, synaptic uptake density, oxidative glucose intake, deficient striatal lactate accumulation and chronic inflammation. Over the last decade, novel bioproducts have received considerable interest due to their unique potential of unifying nutritional, safety and therapeutic natural effects. Some nutraceuticals play a crucial role in the control of the signaling transduction pathways in neurotransmission and inflammation affected in PD, and some natural compounds can beneficially interact with each one of these biological mechanisms to slow down disease progression. Atremorine, a novel plant-derived nutraceutical, probably with a neuroprotective effect in the dopaminergic neurons of the substantia nigra (pars compacta), is a prototype of this new category of bioproducts with potential effects in PD. The major focus of this review will be on the current knowledge and biomedical investigation strategies through a plant-derived neuroprotective approach to improve life quality in PD patients, being of paramount importance for health providers, caregivers and the patients themselves.

Neurotrophic and cholinergic treatment in Alzheimer's disease: Results of a randomized clinical trial

P3-448 NEUROTROPHIC AND CHOLINERGIC TREATMENT IN ALZHEIMER’S DISEASE: RESULTS OF A RANDOMIZED CLINICAL TRIAL Anton Alvarez, Carolina Sampedro, Veronica Couceiro, Ramon Cacabelos, Manuel Aleixandre, Carlos Linares, Elias Granizo, Edith Doppler, Philipp Novak, Herbert Moessler, Euroespes Biomedical Research Centre, a Coruña, Spain; Faculty of Psychology, Granada University, Granada, Spain; Memory Clinic, Malaga, Spain; Ever Neuro Pharma, Unterach, Austria. Contact e-mail: xantonal@yahoo.es

Opposite effects of cerebrolysin on serum TNF-alpha and IGF-I levels in Alzheimer's disease

Background: Post hoc analyses of placebo-controlled studies suggest that memantine treatment may benefit language and conversation abilities of patients’ with Alzheimer’s disease (AD). This study prospectively evaluated the effects of memantine on functional communication in patients with moderate AD. Methods: Native English-speaking outpatients (N1⁄4265) with AD (MMSE range: 10-19) participated in a 12-week, international, double-blind, randomized, placebo-controlled study of memantine (20 mg/day) versus placebo. Concurrent cholinesterase inhibitor treatment, stable throughout the study, was permitted but not required. The primary outcome was the baseline-to-endpoint score change on the Functional Linguistic Communication Inventory (FLCI), a patient performance measure; secondary outcome was the baseline-to-endpoint score change on the combined Social Communication and Communication of Basic Needs subscales of the American SpeechLanguage-Hearing Association Functional Assessment Communication Skills for Adults (ASHA FACS), a caregiver assessment. Primary analysis was based on the intent-to-treat population and the last observation carried forward (LOCF) approach, performed using a two-way ANCOVA model with treatment group and study center as factors, and baseline score as covariate. Further analyses were based on the observed cases (OC) and the mixed-effects model with repeated measures (MMRM; FLCI only). Safety and tolerability were assessed by recording treatment-emergent adverse events (TEAEs). Results: Patients treated with memantine (n1⁄4133) demonstrated a statistically significant (LOCF) improvement on the FLCI at Weeks 4 and 8, and trend at Week 12 (placebo: -0.6; memantine: 0.7; P1⁄40.070) when compared with patients treated with placebo (n1⁄4124); improvement on the ASHA FACS was significant at Weeks 8 and 12 (placebo: -5.3; memantine: 0.5; P1⁄40.022). Analyses based on OC (FLCI; ASHA FACS) and MMRM (FLCI) yielded similar results. Memantine was well tolerated; only dizziness and restlessness were reported by 2% of memantine patients and at an incidence twice that observed in the placebo group. Conclusions: Treatment of patients with moderate AD with memantine improves functional communication skills which can be recognized by caregivers.

O2-03-08: Hyperactivity of peripheral TNF-alpha system in Alzheimer's disease: Interaction with serum IGF-I

with amyloid -peptide (A ) has been proposed as a treatment for AD. Experimental models have shown that A accumulation in the brain, a key feature of the disease, can be reversed by immunotherapy mediated, at least in part, by phagocytosis by microglia (cells of the monocyte/macrophage lineage). Methods: We are co-ordinating a collaborative clinical and neuropathological follow-up of the patients who where in the first trial of active A immunization (Elan Pharmaceuticals). To date we have neuropathology on 9 immunized AD patients (iAD) who died between 4 and 64 months after first immunization dose. In these cases we have quantified the expression of microglial proteins, compared with unimmunized AD controls. Results: CD68 is a component of the wall of lysosomes and its presence is therefore an indication of phagocytic activity. A similar amount of CD68 immunostaining was observed in cerebral cortex of both the iAD cases and AD controls indicating phagocytic activity in both groups. The iAD cases showed variable degrees of plaque clearance associated with A within the lysosomes of activated microglia, indicating that A had been phagocytosed. However, the phagocytic activity in the AD controls was not associated with A within microglia, suggesting that microglia are qualitatively different after immunization. Conclusions: These observations highlight the point that, rather than simply demonstrating that microglia have been activated, it is the specific way in which microglia are activated that is important in determining their role in AD pathology. To what extent the changes in the activation of microglia are reflected in changes in cognitive function, remains to be determined. Indeed despite evidence of plaque removal, mediated at least in part by microglia, all except one of the iAD patients studied at post mortem had severe end stage dementia prior to death.