Effects of acute ethanol and/or diazepam exposure on immediate and delayed hippocampal metabolite levels in rats anesthetized with isoflurane.

Alcohol and benzodiazepines are psychoactive substances frequently associated in voluntary drug intoxications that share common mechanisms of action, including facilitation of GABAergic transmission. This study aimed to assess the separate and combined effects of ethanol and diazepam acute exposure on hippocampal metabolite levels, as well as on delayed cognitive performance, in rats anesthetized with isoflurane. Adult male Wistar rats received one intraperitoneal injection containing either saline solution ("CTL" group, N = 15), a 5-mg/kg dose of diazepam ("DIA" group, N = 16), a 2-g/kg dose of ethanol ("EtOH" group, N = 18), or a 5-mg/kg dose of diazepam + a 2-g/kg dose of ethanol ("DIA + EtOH" group, N = 24). The levels of brain metabolites in the hippocampal region were assessed using in vivo magnetic resonance spectroscopy (MRS) before and after injection. Behavioral testing, including working memory and visual recognition memory assessment, was performed at week 3, while a new MRS acquisition was conducted 4 weeks after the injection. In the hour following acute exposure, a decrease in glutamate levels was found in the DIA + EtOH group only. Four weeks after injection, a decrease in GABA and glutamate levels and an increase in NAA levels were found in the EtOH group only. No significant between-group differences were found in the behavioral assessment. While the initial decrease in glutamate levels in the DIA + EtOH group suggests an early potentiation effect between ethanol and diazepam, the long-term modifications found only in the EtOH group suggest a possible downregulation of ethanol's effect by diazepam at 4 weeks.

Lack of direct involvement of a diazepam long-term treatment in the occurrence of irreversible cognitive impairment: a pre-clinical approach.

Several observational studies have found a link between the long-term use of benzodiazepines and dementia, which remains controversial. Our study was designed to assess (i) whether the long-term use of benzodiazepines, at two different doses, has an irreversible effect on cognition, (ii) and whether there is an age-dependent effect. One hundred and five C57Bl/6 male mice were randomly assigned to the 15 mg/kg/day, the 30 mg/kg/day diazepam-supplemented pellets, or the control group. Each group comprised mice aged 6 or 12 months at the beginning of the experiments and treated for 16 weeks. Two sessions of behavioral assessment were conducted: after 8 weeks of treatment and after treatment completion following a 1-week wash-out period. The mid-treatment test battery included the elevated plus maze test, the Y maze spontaneous alternation test, and the open field test. The post-treatment battery was upgraded with three additional tests: the novel object recognition task, the Barnes maze test, and the touchscreen-based paired-associated learning task. At mid-treatment, working memory was impaired in the 15 mg/kg diazepam group compared to the control group (p = 0.005). No age effect was evidenced. The post-treatment assessment of cognitive functions (working memory, visual recognition memory, spatial reference learning and memory, and visuospatial memory) did not significantly differ between groups. Despite a cognitive impact during treatment, the lack of cognitive impairment after long-term treatment discontinuation suggests that benzodiazepines alone do not cause irreversible deleterious effects on cognitive functions and supports the interest of discontinuation in chronically treated patients.

Contributions of animal models of cognitive disorders to neuropsychopharmacology.

Cognitive disorders and symptoms are key features of many mental and neurological diseases, with a large spectrum of impaired domains. Because of their possible evolution and detrimental functioning impact, they are a major pharmacological target for both symptomatic and disease-modifier drugs, while few cognitive enhancers have been marketed with an insufficient efficiency. It explains the need to model these cognitive disorders beyond the modelization of mental or neurological diseases themselves. According to the experimental strategy used to induce cognitive impairment, three categories of models have been identified: neurotransmission-driven models; pathophysiology-driven models; environment-driven models. These three categories of models reflect different levels of integration of endogenous and exogenous mechanisms underlying cognitive disorders in humans. Their comprehensive knowledge and illustration of their pharmacological modulation could help to propose a renewing strategy of drug development in central nervous system (CNS) field at a time when the academic and industrial invest seems to be declining despite the medical and social burden of brain diseases.

Drug interactions with dementia-related pathophysiological pathways worsen or prevent dementia.

Many risk factors are known to induce or precipitate dementia. Drugs acting via different mechanisms can modulate cognitive performance and exert either beneficial or deleterious effects on cognition through functional or neuropathological mechanisms. This review discusses the association between several classes of drugs and cognitive impairment and dementia risk. These drugs can be divided into drugs targeting CNS disorders (e.g., anticholinergic drugs, antiepileptics, antipsychotics, benzodiazepines, and opioids) and drugs targeting non-CNS disorders (e.g., antidiabetics, antihypertensives, proton pump inhibitors, and statins). Furthermore, we sought to highlight the pharmacological mechanisms underlying their possible detrimental or beneficial effects on cognition. Anticholinergic and antiepileptic drugs were excluded from this review because their effects on cognition are well known. Studies investigating benzodiazepines have revealed an increased risk of dementia. Conclusions on dementia risk or cognitive impairment regarding opioids and antipsychotic drugs are difficult to draw. These different classes appear to impair cognition not by a single clear mechanism of action specific to each class but by several relatively interdependent and interconnected mechanisms (e.g., impaired neurotransmission, neuroinflammation, neuronal death, oxidative stress, or interactions with dementia-related pathways). The dementia risk initially associated with the use of proton pump inhibitors might have been overestimated. In contrast, statins, antihypertensive medications, and antidiabetics could potentially decrease the risk of dementia and cognitive impairment by acting in ways opposite to the mechanisms cited above. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

Preadmission use of benzodiazepines and stroke outcomes: the Biostroke prospective cohort study.

OBJECTIVES: We tested the hypothesis that stroke outcomes in patients with preadmission use of benzodiazepine are worse. METHOD: In a prospective cohort study, we recruited patients with acute ischaemic stroke. Mortality, functional outcomes and cognition were evaluated at 8 and 90 days after stroke. RESULTS: 370 patients were included. 62 (18.5%) of the 336 remaining patients were treated with benzodiazepines when stroke occurred, and they did not receive any other psychotropic drug. The mortality rate was higher in benzodiazepines users than non-users at day 8 (2.2% vs 8.1%, p=0.034) and day 90 (8.1% vs 25.9%, p=0.0001). After controlling for baseline differences using propensity-score matching, only the difference in mortality rate at day 90 was of borderline of significance, with a matched OR of 3.93 (95% CI, 0.91 to 16.98). In propensity-score-adjusted cohort, this difference remained significant with a similar treatment effect size (adjusted OR, 3.50; 95% CI, 1.57 to 7.76). A higher rate of poor functional outcome at day 8 and day 90 defined bymodified Rankin scale (mRS) ≥2 or by theBarthel index (BI) <95 was found in benzodiazepines users. In propensity-score-adjusted cohort, only the difference in mRS≥2 at day 90 remained significant (adjusted OR, 1.89; 95% CI, 1.02 to 3.48). In survivors at day 8 and at day 90, there was no significant difference in cognitive evaluation. CONCLUSION: Our study has shown that preadmission use of benzodiazepines could be associated with increased post-stroke mortality at 90 days. These findings do not support a putative neuroprotective effect of γ-aminobutyric acidA receptors agonists and should alert clinicians of their potential risks. TRIAL REGISTRATION NUMBER: NCT00763217.

Role of cortical microbleeds in cognitive impairment: In vivo behavioral and imaging characterization of a novel murine model.

Cerebral microbleeds (CMBs) could contribute to cognitive impairment in the general population and in patients with dementia. We designed a study to (i) develop a murine model of CMBs, (ii) assess whether CMBs affect cognition in this model and (iii) assess whether this model is sensitive to pharmacological modulation. Male C57Bl6/J mice were stereotactically administered collagenase to induce cortical lesion analysed by MRI at 24 h. CMB-mice were assessed at six weeks post-lesion for cognitive performances (Barnes maze and Touchscreen automated paired-associated learning (PAL) task) and for cerebral metabolism (in vivo PET/CT with fluorodeoxyglucose (FDG)). CMB-model sensitivity to pharmacological modulation was assessed by administering atorvastatin (5 mg/kg/day) over the follow-up period. CMB mice were compared to naïve littermates. Collagenase at 0.8 µU/µl appeared suitable to induce reproducible and reliable CMBs. At six weeks, a decline in learning, spatial and visuospatial memory was significantly observed in CMB-mice. Brain metabolism was impaired in all cortex, striatum and the ipsilateral dentate gyrus. A significant improvement in cognition performances was depicted under atorvastatin. In this novel murine model of CMBs, we validated that CMBs lowered cognitive performances and affected regional metabolism. We also proved that this CMB-model is sensitive to pharmacological modulation.

A 15-day course of donepezil modulates spectral EEG dynamics related to target auditory stimuli in young, healthy adult volunteers.

OBJECTIVE: To identify possible electroencephalographic (EEG) markers of donepezil's effect on cortical activity in young, healthy adult volunteers at the group level. METHODS: Thirty subjects were administered a daily dose of either 5mg donepezil or placebo for 15days in a double-blind, randomized, cross-over trial. The electroencephalogram during an auditory oddball paradigm was recorded from 58 scalp electrodes. Current source density (CSD) transformations were applied to EEG epochs. The event-related potential (ERP), inter-trial coherence (ITC: the phase consistency of the EEG spectrum) and event-related spectral perturbation (ERSP: the EEG power spectrum relative to the baseline) were calculated for the target (oddball) stimuli. RESULTS: The donepezil and placebo conditions differed in terms of the changes in delta/theta/alpha/beta ITC and ERSP in various regions of the scalp (especially the frontal electrodes) but not in terms of latency and amplitude of the P300-ERP component. CONCLUSION: Our results suggest that ITC and ERSP analyses can provide EEG markers of donepezil's effects in young, healthy, adult volunteers at a group level. SIGNIFICANCE: Novel EEG markers could be useful to assess the therapeutic potential of drug candidates in Alzheimer's disease in healthy volunteers prior to the initiation of Phase II/III clinical studies in patients.

Regulation of Protein Synthesis and Apoptosis in Lymphocytes of Parkinson Patients: The Effect of Dopaminergic Treatment.

BACKGROUND: Parkinson disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of the dopaminergic neurons in the substantia nigra, presumably due to increased apoptosis. In previous studies, we showed altered expression of proteins involved in mammalian target of rapamycin (mTOR) antiapoptotic and double-stranded RNA-dependent protein kinase (PKR) apoptotic pathways of translational control in experimental cellular and animal models of PD. RESULTS: In this work, our results showed clear modifications in the expression of kinases involved in mTOR and PKR apoptosis pathways, in lymphocytes of PD patients treated or not with anti-PD treatment (levodopa), which confirmed the role played by apoptosis in the pathogenesis of this disease and the positive effect of treatment with medication on this parameter. Others proteins involved in apo-ptosis were also evaluated in lymphocytes of patients as the expression of the peripheral benzodiazepine receptor and caspase-3. CONCLUSION: Translational control is altered in PD and hence its evaluation in peripheral blood mononuclear cells may serve as an early marker of apoptosis and indicate the efficacy of the dopaminergic treatment.

Translational Challenge Models in Support of Efficacy Studies: Effect of Cerebral Hypoxia on Cognitive Performances in Rodents.

Empirical evidence currently supports the idea that neurovascular dysfunction is involved in the neurodegenerative process of Alzheimer's disease (AD). In fact, epidemiological studies report that i) vascular risk factors are directly associated with an increased incidence of AD and ii) vascular lesions are frequently co-existent with AD. The neurovascular unit is a key control system for oxygen and nutrients exchange between neurons and microvessels so the integrity of this system is essential for neuronal activity and cell survival. This suggests that hypoxia arising from various vascular injuries may participate in the pathogenesis of AD and aggravate cognitive deficit. Moreover, hypoxia appears to have a direct effect on cognitive functions, in particular memory, by inducing a transient or definitive dysfunction of synaptic transmission. The interplay of hypoxic phenomenon and the development of AD-related pathologies support the use of hypoxia as a challenge model to assess symptomatic (i.e. cognitive enhancers) AD-treatment. Such challenge should be characterized and validated with current symptomatic drugs based on different mechanisms of action before being offered as alternative models for testing new drugs. To date, symptomatic treatments of AD including anticholinesterasic- (donepezil, rivastigmine and galantamine) and antiglutamatergic- (memantine) drugs target various neurotransmission impairments occurring at different stages of the disease. The first aim of the present review is to provide an overview of the methods used to achieve experimental hypoxia in rodents and to characterize the cognitive alterations induced by each method. The second objective is to summarize the main results from studies that have tested the effect of acetylcholinesterase inhibitors on hypoxiainduced cognitive impairment. Overall, the literature research yielded only a small number of studies investigating the effect of hypoxia on cognition in rodents and the different models described sometime differ substantially in terms of timing, severity and nature of cognitive impairment. Chronic exposure to intermittent normobaric or continuous hypobaric hypoxia induced persistent spatial reference and working memory alterations. In contrast, acute hypoxia exposure was shown to induce more transient associative and spatial memory impairments. Treatment with acetylcholinesterase inhibitors was shown to improve hypoxia-induced memory impairment in various hypoxia protocols.

Neurobehavioral and Cognitive Changes Induced by Sleep Deprivation in Healthy Volunteers.

To this day, the pharmacological treatment of Alzheimer's disease remains limited to the temporary stabilisation of cognitive decline and the reduction of neuropsychiatric symptoms. It is moreover with great difficulty to predict and select promising drug candidates in the early stages of the discovery and developmental process. In this context, scientists have developed new experimental paradigms to artificially induce transient cognitive impairments in healthy volunteers akin to those observed in Alzheimer's disease, i.e. the Cognitive Challenge Models. In the last decade, a great amount of literature on Sleep Deprivation was published which mainly focused on the consequences of sleep loss for public health. However, sleep deprivation paradigm may also be regarded as a cognitive challenge model. It is commonly accepted that sleep deprivation induces cognitive impairments related to a global decrease in vigilance, while in fact, there is a controversial approach related to the selective effects on cognitive functions. The identification and validation of cognitive challenge models in healthy volunteers are suitable in early clinical development of drugs to determine the 'hint of efficacy' of drug candidates. The present review aims at exploring in detail the methods, designs and cognitive paradigms used in non pharmacological sleep deprivation studies. Sleep deprivation can be induced by different methods. Probing the four main cognitive functions will allow identifying the extent to which different sleep deprivation designs selectively compromise executive function, working memory, episodic memory and attention. Findings will be discussed in line with cognitive processing levels that are required according to the tasks.

Early Development of Symptomatic Drugs in AD: A Systematic Review of the Use of Biomarkers.

Pharmacological therapies currently marketed for Alzheimer's disease (AD) are only symptomatic and show limited effects in terms of clinical benefit. Thus, the development of new symptomatic drugs remains essential. However the dramatic increase in costs associated with drug development together with the poor number of emerging drugs highlights how crucial it is to accelerate the findings aiming to bringing new drugs to market. In this respect, optimization of the development process by integrating, at early stage, reliable biomarkers able to predict clinical benefit in phase III clinical trials may help. The improvement of certain techniques such as imaging and electrophysiological methods has led to a more accurate assessment of the brain's physiological impact of pharmacological treatments used to alleviate symptoms in AD patients. This review aims to gather the main findings from clinical studies where the effect of anti-dementia drugs were assessed in healthy volunteers and AD patients through one or several such biomarkers (electroencephalography (EEG), magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT)). Overall, evidence presented in this review suggests that various biomarkers associated with key impairments observed in AD were sensitive to acetylcholinesterase inhibitors (AChE-I) medication and memantine with a good correlation with enhancement of cognitive performance. In most of the reviewed studies, only one kind of biomarker was used. Among these, deficits in quantitative EEG profile, P300 latency, and regional brain activity measured by either functional MRI (fMRI) during face encoding and working memory task or by PET/SPECT have been shown to be reversed by anti-dementia drugs. It is therefore suggested that a single biomarker approach would be limited and not be sufficiently predictive to extensively assess the potential of a new symptomatic drug. Hence, it appears that a combination approach with the use of a panel of biomarkers rather than a single biomarker may be more appropriate to establish a good correlation between the disease and therapeutic intervention.

Neurobehavioral and Cognitive Changes Induced by Hypoxia in Healthy Volunteers.

The early assessment of new symptomatic drugs against Alzheimer's disease remains difficult because of the lack of a predictive end-point. The use of a battery including different parameters could improve this early development. In order to test the reverse effect of symptomatic drugs in healthy volunteers, scientists have developed new experimental paradigms to artificially induce transient cognitive impairments in healthy volunteers akin to those observed in Alzheimer's disease, i.e. Cognitive Challenge Models. In this context, transient hypoxia could be a relevant Cognitive Challenge Model. The deleterious effects of hypoxia on cognition, as described in the literature, should be considered carefully since they are usually assessed with different populations that do not have the same hypoxic sensitivity. Hypoxia can be obtained by the means of two different methods: normobaric and hypobaric hypoxia. In both designs, cognitive changes can be directly modulated by the severity of hypoxic levels. The purpose of this review is to gather existing support on the application of hypoxia within different cognitive domains and to highlight the scientific interests of such a model to predict and select promising drug candidates. We aimed at reviewing in detail the methods, designs and cognitive paradigms used in non-pharmacological hypoxia studies. Probing the four main cognitive functions will allow identifying the extent to which different hypoxia designs selectively compromise cognitive functioning. For each cognitive process, the convergent and divergent results are discussed in terms of paradigm differences whereas we will focus on defining the optimal methodology for obtaining the desired effects.

Donepezil increases contrast sensitivity for the detection of objects in scenes.

We assessed the effects of donepezil, a drug that stimulates cholinergic transmission, and scopolamine, an antagonist of cholinergic transmission, on contrast sensitivity. 30 young male participants were tested under three treatment conditions: placebo, donepezil, and scopolamine in a random order. Pairs of photographs varying in contrast were displayed left and right of fixation for 50 ms. Participants were asked to locate the scene containing an animal. Accuracy was better under donepezil than under scopolamine, particularly for signals of high intensity (at higher levels of contrast). A control experiment showed that the lower performance under scopolamine did not result from the mydriasis induced by scopolamine. The results suggest that cholinergic stimulation, through donepezil, facilitates signal detection in agreement with studies on animals showing that the pharmacological activation of cholinergic receptors controls the gain in the relationship between the stimulus contrast (intensity of the visual input) and visual response. As Alzheimer disease is associated to depletion in acetylcholine, and there is evidence of deficits in contrast sensitivity in Alzheimer, it might be interesting to integrate such rapid and sensitive visual tasks in the biomarkers at early stage of drug development.

Cholinergic modulation of stimulus-driven attentional capture.

Distraction is one of the main problems encountered by people with degenerative diseases that are associated with reduced cortical cholinergic innervations. We examined the effects of donepezil, a cholinesterase inhibitor, on stimulus-driven attentional capture. Reflexive attention shifts to a distractor are usually elicited by abrupt peripheral changes. This bottom-up shift of attention to a salient item is thought to be the result of relatively inflexible hardwired mechanisms. Thirty young male participants were randomly allocated to one of two groups: placebo first/donepezil second session or the opposite. They were asked to locate a target appearing above and below fixation whilst a peripheral distractor moved abruptly (motion-jitter attentional capture condition) or not (baseline condition). A classical attentional capture effect was observed under placebo: moving distractors interfered with the task in slowing down response times as compared to the baseline condition with fixed distractors. Increased interference from moving distractors was found under donepezil. We suggest that attentional capture in our paradigm likely involved low level mechanisms such as automatic reflexive orienting. Peripheral motion-jitter elicited a rapid reflexive orienting response initiated by a cholinergic signal from the brainstem pedunculo-pontine nucleus that activates nicotinic receptors in the superior colliculus.

Therapeutic prospects of PPARs in psychiatric disorders: a comprehensive review.

Peroxisome Proliferator-Activated Receptors (PPARs) are a family of nuclear receptors whose activation modulates the gene expression that underlies both the glucid-lipid and the inflammation pathways. While many PPARs agonists have been used for years as medication for metabolic disorders, an increasing attention is being currently dedicated to these drugs for inflammation-related pathologies. Within the psychiatric field, it has recently appeared that inflammatory processes are highly suspected in the pathophysiology of several important disorders, such as schizophrenia and mood disorders. By their anti-inflammatory properties, PPARs might have a disease-modifying action that could help in improving the outcome of patients. Furthermore, recent data suggest that PPARs could also modulate the expression of some neurotransmission factors. Therefore, PPARs may directly modify the information processing, and have a potential symptomatic action on several psychiatric disorders. At last, PPARs action of metabolic regulation could have a role on corrective or even preventive strategies against the metabolic adverse events that are commonly observed with some current psychiatric medications, notably antipsychotics. This triple potential action profile of PPARs modulators is investigated in this article, successively for schizophrenia spectrum disorders and mood disorders. Theoretical involvements of PPARs are also discussed for the treatment of Post- Traumatic Stress Disorder and Personality Disorders. At the time of the emerging concept of psychoneuroimmunology, PPARs open original therapeutic prospects for the psychiatric research.

Modulation of lipid-induced ER stress by fatty acid shape.

Exposure of pancreatic ß cells to long-chain saturated fatty acids (SFA) induces a so-called endoplasmic reticulum (ER) stress that can ultimately lead to cell death. This process is believed to participate in insulin deficiency associated with type 2 diabetes, via a decrease in ß-cell mass. By contrast, some unsaturated fatty acid species appear less toxic to the cells and can even alleviate SFA-induced ER stress. In the present study, we took advantage of a simple yeast-based model, which brings together most of the trademarks of lipotoxicity in human cells, to screen fatty acids of various structures for their capacity to counter ER stress. Here we demonstrate that the tendency of a free fatty acid (FFA) to reduce SFA toxicity depends on a complex conjunction of parameters, including chain length, level of unsaturation, position of the double bonds and nature of the isomers (cis or trans). Interestingly, potent FFA act as building blocks for phospholipid synthesis and help to restore an optimal membrane organization, compatible with ER function and normal protein trafficking.

Time course of MPTP toxicity on translational control protein expression in mice brain.

The present study investigated in mice brain, the time course of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity on the expression of translational control proteins. Mice received intraperitoneal injections of MPTP (30 mg/kg/day) for 5 days and were sacrificed 1, 2, 3, 4 and 7 days after the last injection. The results, obtained by western blot, indicated that MPTP produced an alteration of the expression of proteins involved in the mTOR anti-apoptotic way and the PKR pro-apoptotic pathway of translational control especially in striatum and frontal cortex of mice. These disturbances were associated with a great activation of PKR in hippocampus at D9, the time point corresponding to maximal translational control alterations. Furthermore, whereas no modification of translational control protein expression was observed in mice substantia nigra after western blot procedure, immunofluorescent labeling revealed, in this target region of the toxin MPTP, a decrease of the expression of phospho-mTOR and a great activation of the phosphorylated form of PKR, marker of pathogenesis.

Neuroprotective effect of PACAP on translational control alteration and cognitive decline in MPTP parkinsonian mice.

Parkinson's disease (PD) is characterized by a triade of motor symptoms due to the degeneration of nigrostriatal pathway. In addition to these motor impairments, cognitive disturbances have been reported to occur in PD patients in the early stage of the disease. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin widely used to produce experimental models of PD. In a previous work, we showed that MPTP altered the expression of proteins involved in mTOR antiapoptotic and PKR apoptotic pathways of translational control (TC) in neuroblastoma cells. In the present study, the results indicated that a subchronic MPTP intoxication in mice decreased the dopaminergic neuron number, produced an activation of PKR way and an inhibition of mTOR way of TC especially in striatum and frontal cortex associated with a great activation of PKR in hippocampus. Moreover, in parallel to biochemical analysis, the mnesic disturbances induced by MPTP were characterized in C57Bl/6 mice, by testing their performance in three versions of the Morris Water Maze task. Behavioral results showed that the MPTP lesion altered mice learning of a spatial working memory, of a cued version and of a spatial reference memory task in the water maze. Furthermore, we previously demonstrated that the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) could counteract the MPTP toxicity on TC factors in neuroblastoma cells. Thus, the second objective of our study was to assess the PACAP effect on MPTP-induced TC impairment and cognitive deficit in mice. The pretreatment with PACAP27 by intravenous injections partially protected TH-positive neuron loss induced by MPTP, prevented the MPTP-induced protein synthesis control dysregulation and mnesic impairment of mice. Therefore, our results could indicate that PACAP may be a promising therapeutic agent in Parkinson's disease.