Animal Models Of Neurodegenerative Disorders Research Articles

Resolving a paradox: antidepressants, neuroinflammation, and neurodegeneration

Depression is a known risk factor for dementia. Antidepressants are the most commonly used treatment for this condition, and are effective in at least half to two-thirds of cases. Extensive evidence from in vitro and animal models suggests that antidepressants have anti-inflammatory and neuroprotective properties. These effects have been shown to reduce the oxidative damage, amyloid aggregation, and expression of pro-inflammatory genes associated with animal models of neurodegenerative disorders. However, longitudinal research in humans has shown that antidepressants do not protect against dementia, and may even be associated with a risk of cognitive deterioration over time in older adults. The contrast between two sets of findings represents a paradox of significant clinical and public health significance, particularly when treating depression in late life. This review paper attempts to resolve this paradox by critically reviewing the medium- and long-term effects of antidepressants on peripheral immune-inflammatory responses, infection risk, gut microbiota, and neuroendocrine responses to stress, and how these effects may influence the risk of neurodegeneration. Briefly stated, it is possible that the peripheral actions of antidepressant medications may antagonize their beneficial effects against neuroinflammation. The implications of these findings are then explored with a particular focus on the development and testing of multimodal neuroprotective and anti-inflammatory treatments that could reduce the risk of Alzheimer’s and related dementias in patients suffering from depression.

Hypericum perforatum: a comprehensive review on pharmacognosy, preclinical studies, putative molecular mechanism, and clinical studies in neurodegenerative diseases.

The herb Hypericum perforatum, also referred to as St. John's wort, has drawn a lot of interest because of its potential therapeutic benefits in treating neurodegenerative illnesses. Due to the absence of effective therapies, illnesses like Alzheimer's and Parkinson's disease pose an increasing worldwide health concern. Because of its wide variety of phytochemicals, especially hyperforin, and hypericin, Hypericum perforatum is well known for its neuroprotective properties. These substances have proven to be able to affect different cellular processes linked to neurodegeneration. They can act as anti-inflammatory, antioxidant, and neurotransmitter system regulators, which may help halt neurodegenerative illnesses' progression. The use of Hypericum perforatum extracts and its contents has shown encouraging results in research on animal models of neurodegenerative disorders. These advantages include higher nerve cell survival, lowered oxidative stress, and higher cognitive performance. Underscoring its versatile potential to combat neurodegeneration, Hypericum perforatum has neuroprotective mechanisms that modulate neuroinflammation and prevent apoptotic pathways. In conclusion, Hypericum perforatum shows tremendous promise as a potential treatment for neurological illnesses due to its wide variety of phytochemicals. To completely comprehend its specific mechanisms of action and turn these discoveries into efficient clinical therapies, additional research is needed. Investigating Hypericum perforatum's function in neurodegenerative disorders may present new opportunities for the advancement of ground-breaking therapeutic strategies.

Molecular Mechanism Operating in Animal Models of Neurogenic Detrusor Overactivity: A Systematic Review Focusing on Bladder Dysfunction of Neurogenic Origin

Neurogenic detrusor overactivity (NDO) is a severe lower urinary tract disorder, characterized by urinary urgency, retention, and incontinence, as a result of a neurologic lesion that results in damage in neuronal pathways controlling micturition. The purpose of this review is to provide a comprehensive framework of the currently used animal models for the investigation of this disorder, focusing on the molecular mechanisms of NDO. An electronic search was performed with PubMed and Scopus for literature describing animal models of NDO used in the last 10 years. The search retrieved 648 articles, of which reviews and non-original articles were excluded. After careful selection, 51 studies were included for analysis. Spinal cord injury (SCI) was the most frequently used model to study NDO, followed by animal models of neurodegenerative disorders, meningomyelocele, and stroke. Rats were the most commonly used animal, particularly females. Most studies evaluated bladder function through urodynamic methods, with awake cystometry being particularly preferred. Several molecular mechanisms have been identified, including changes in inflammatory processes, regulation of cell survival, and neuronal receptors. In the NDO bladder, inflammatory markers, apoptosis-related factors, and ischemia- and fibrosis-related molecules were found to be upregulated. Purinergic, cholinergic, and adrenergic receptors were downregulated, as most neuronal markers. In neuronal tissue, neurotrophic factors, apoptosis-related factors, and ischemia-associated molecules are increased, as well as markers of microglial and astrocytes at lesion sites. Animal models of NDO have been crucial for understanding the pathophysiology of lower urinary tract (LUT) dysfunction. Despite the heterogeneity of animal models for NDO onset, most studies rely on traumatic SCI models rather than other NDO-driven pathologies, which may result in some issues when translating pre-clinical observations to clinical settings other than SCI.

Molecular mechanisms underlying the neuroprotection of environmental enrichment in Parkinson's disease.

Parkinson's disease is the most common movement disorder, affecting about 1% of the population over the age of 60 years. Parkinson's disease is characterized clinically by resting tremor, bradykinesia, rigidity and postural instability, as a result of the progressive loss of nigrostriatal dopaminergic neurons. In addition to this neuronal cell loss, Parkinson's disease is characterized by the accumulation of intracellular protein aggregates, Lewy bodies and Lewy neurites, composed primarily of the protein α-synuclein. Although it was first described almost 200 years ago, there are no disease-modifying drugs to treat patients with Parkinson's disease. In addition to conventional therapies, non-pharmacological treatment strategies are under investigation in patients and animal models of neurodegenerative disorders. Among such strategies, environmental enrichment, comprising physical exercise, cognitive stimulus, and social interactions, has been assessed in preclinical models of Parkinson's disease. Environmental enrichment can cause structural and functional changes in the brain and promote neurogenesis and dendritic growth by modifying gene expression, enhancing the expression of neurotrophic factors and modulating neurotransmission. In this review article, we focus on the current knowledge about the molecular mechanisms underlying environmental enrichment neuroprotection in Parkinson's disease, highlighting its influence on the dopaminergic, cholinergic, glutamatergic and GABAergic systems, as well as the involvement of neurotrophic factors. We describe experimental pre-clinical data showing how environmental enrichment can act as a modulator in a neurochemical and behavioral context in different animal models of Parkinson's disease, highlighting the potential of environmental enrichment as an additional strategy in the management and prevention of this complex disease.

Mitochondria: how eminent in ageing and neurodegenerative disorders?

Numerous factors are implicated in the onset and progression of ageing and neurodegenerative disorders, with defects in cell energy supply and free radicals regulation designated as being the main functions of mitochondria and highly accentuated in plentiful studies. Hence, analysing the role of mitochondria as one of the main factors implicated in these disorders could undoubtedly come in handy with respect to disease prevention and treatment. In this review, first, we will explore how mitochondria account for neurodegenerative disorders and ageing and later will draw the various pathways contributing to mitochondrial dysfunction in their distinct way. Also, we will discuss the deviation-countering mechanisms, particularly mitophagy, a subset of autophagy known as a much larger cellular defence mechanism and regulatory system, along with its potential therapeutic effects. Last but not least, we will be highlighting the mitochondrial transfer experiments with animal models of neurodegenerative disorders.

PET Imaging of Synaptic Density: Challenges and Opportunities of Synaptic Vesicle Glycoprotein 2A PET in Small Animal Imaging.

The development of novel PET imaging agents for synaptic vesicle glycoprotein 2A (SV2A) allowed for the in vivo detection of synaptic density changes, which are correlated with the progression and severity of a variety of neuropsychiatric diseases. While multiple ongoing clinical investigations using SV2A PET are expanding its applications rapidly, preclinical SV2A PET imaging in animal models is an integral component of the translation research and provides supporting and complementary information. Herein, we overview preclinical SV2A PET studies in animal models of neurodegenerative disorders and discuss the opportunities and practical challenges in small animal SV2A PET imaging. At the Yale PET Center, we have conducted SV2A PET imaging studies in animal models of multiple diseases and longitudinal SV2A PET allowed us to evaluate synaptic density dynamics in the brains of disease animal models and to assess pharmacological effects of novel interventions. In this article, we discuss key considerations when designing preclinical SV2A PET imaging studies and strategies for data analysis. Specifically, we compare the brain imaging characteristics of available SV2A tracers, i.e., [11C]UCB-J, [18F]SynVesT-1, [18F]SynVesT-2, and [18F]SDM-16, in rodent brains. We also discuss the limited spatial resolution of PET scanners for small brains and challenges of kinetic modeling. We then compare different injection routes and estimate the maximum throughput (i.e., number of animals) per radiotracer synthesis by taking into account the injectable volume for each injection method, injected mass, and radioactivity half-lives. In summary, this article provides a perspective for designing and analyzing SV2A PET imaging studies in small animals.

Neuroprotection by the Ketogenic Diet: Evidence and Controversies.

The ketogenic diet (KD) is a high-fat low-carbohydrate diet that has been used for decades as a non-pharmacologic approach to treat metabolic disorders and refractory pediatric epilepsy. In recent years, enthusiasm for the KD has increased in the scientific community due to evidence that the diet reduces pathology and improves various outcome measures in animal models of neurodegenerative disorders, including multiple sclerosis, stroke, glaucoma, spinal cord injury, retinal degenerations, Parkinson's disease and Alzheimer's disease. Clinical trials also suggest that the KD improved quality of life in patients with multiple sclerosis and Alzheimer's disease. Furthermore, the major ketone bodies BHB and ACA have potential neuroprotective properties and are now known to have direct effects on specific inflammatory proteins, transcription factors, reactive oxygen species, mitochondria, epigenetic modifications and the composition of the gut microbiome. Neuroprotective benefits of the KD are likely due to a combination of these cellular processes and other potential mechanisms that are yet to be confirmed experimentally. This review provides a comprehensive summary of current evidence for the effectiveness of the KD in humans and preclinical models of various neurological disorders, describes molecular mechanisms that may contribute to its beneficial effects, and highlights key controversies and current gaps in knowledge.

Zebrafish Models of Autosomal Recessive Ataxias.

Autosomal recessive ataxias are much less well studied than autosomal dominant ataxias and there are no clearly defined systems to classify them. Autosomal recessive ataxias, which are characterized by neuronal and multisystemic features, have significant overlapping symptoms with other complex multisystemic recessive disorders. The generation of animal models of neurodegenerative disorders increases our knowledge of their cellular and molecular mechanisms and helps in the search for new therapies. Among animal models, the zebrafish, which shares 70% of its genome with humans, offer the advantages of being small in size and demonstrating rapid development, making them optimal for high throughput drug and genetic screening. Furthermore, embryo and larval transparency allows to visualize cellular processes and central nervous system development in vivo. In this review, we discuss the contributions of zebrafish models to the study of autosomal recessive ataxias characteristic phenotypes, behavior, and gene function, in addition to commenting on possible treatments found in these models. Most of the zebrafish models generated to date recapitulate the main features of recessive ataxias.

CRISPR/Cas9 Technology as a Modern Genetic Manipulation Tool for Recapitulating of Neurodegenerative Disorders in Large Animal Models.

Neurodegenerative diseases are often the consequence of alterations in structures and functions of the Central Nervous System (CNS) in patients. Despite obtaining massive genomic information concerning the molecular basis of these diseases and since the neurological disorders are multifactorial, causal connections between pathological pathways at the molecular level and CNS disorders development have remained obscure and need to be elucidated to a great extent. Animal models serve as accessible and valuable tools for understanding and discovering the roles of causative factors in the development of neurodegenerative disorders and finding appropriate treatments. Contrary to rodents and other small animals, large animals, especially non-human primates (NHPs), are remarkably similar to humans; hence, they establish suitable models for recapitulating the main human's neuropathological manifestations that may not be seen in rodent models. In addition, they serve as useful models to discover effective therapeutic targets for neurodegenerative disorders due to their similarity to humans in terms of physiology, evolutionary distance, anatomy, and behavior. In this review, we recommend different strategies based on the CRISPR-Cas9 system for generating animal models of human neurodegenerative disorders and explaining in vivo CRISPR-Cas9 delivery procedures that are applied to disease models for therapeutic purposes. With the emergence of CRISPR/Cas9 as a modern specific gene-editing technology in the field of genetic engineering, genetic modification procedures such as gene knock-in and knock-out have become increasingly easier compared to traditional gene targeting techniques. Unlike the old techniques, this versatile technology can efficiently generate transgenic large animal models without the need to complicate lab instruments. Hence, these animals can accurately replicate the signs of neurodegenerative disorders. Preclinical applications of CRISPR/Cas9 gene-editing technology supply a unique opportunity to establish animal models of neurodegenerative disorders with high accuracy and facilitate perspectives for breakthroughs in the research on the nervous system disease therapy and drug discovery. Furthermore, the useful outcomes of CRISPR applications in various clinical phases are hopeful for their translation to the clinic in a short time.

USP14 as a Therapeutic Target Against Neurodegeneration: A Rat Brain Perspective.

In the recent past, many of the deubiquitinases (DUB) were found to modulate mitochondrial clearance or mitophagy and thus they are currently projected as therapeutic targets against neurodegeneration. Among these DUBs, USP14 stands at a distinctive juncture, since it can influence both proteasome complex activity and autophagy process. USP14 interference can enhance mitochondrial clearance and thus can protect Parkinsonian phenotypes in Drosophila model. However, in higher animal models of neurodegenerative disorders, evaluation of the protective role of USP14 is yet to be done. In this perspective, we pointed out a few of the major considerations that should be classified before designing experiments to evaluate the therapeutic potential of this DUB in rodent models of neurodegeneration. These are mainly: level of USP14 in the concerned brain region and how the level alters in the model system. Because USP14 mediated mitophagy is Prohibitin2 dependent, the anticipated impact of this protein in this aspect is also discussed. To illustrate our view, we show that USP14 levels increases in adult rat brain substantia nigra (SN) and cerebellum compared to the young ones. We also depict that rotenone treatment can immediately lead to increased SN specific USP14 levels. Our perception thus portrays USP14 as a therapeutic target, especially for addressing SN specific neurodegeneration in adult rat brain, but may vary with the disease model.

The TrkB agonist 7,8-dihydroxyflavone improves sensory-motor performance and reduces lipid peroxidation in old mice.

7,8-Dihydroxyflavone (7,8-DHF) is a natural flavonoid compound that act as Trk-B agonist. 7,8-DHF is also a potent antioxidant. When applied systematically, 7,8-DHF can pass through blood-brain barrier and exhibit potential therapeutic effects in several animal models of neurodegenerative disorders. This study investigates the remedial effects of 7,8-DHF on behavioral impairments and biochemical changes associated with aging with a species emphasis on cortex. For this purpose three experimental groups were formed which are young control group, old group and old-DHF groups. 5 mg/kg 7,8-DHF was administered intraperitoneally to old-DHF group for 3 weeks. We assessed the hang wire and adhesive removal performances of mice. Also, oxidative stress, neuroinflammation and synaptic protein levels in the cortex were measured. We observed that chronic administration of 7,8-DHF improved behavioral performance of old mice. Besides, 7,8-DHF reversed MDA level which was increased in old control animals. However, 3 weeks application of 7,8-DHF failed to recover the levels of neuroinflammation markers (TNF-α and IL-6) and synaptic proteins (PSD-95 and Synaptophysin) which were reduced in old group. These findings demonstrate that improvement of age-dependent behavioral impairments and MDA levels by 7,8-DHF could be attributed to its antioxidant actions.

Different faces of neurodegeneration.

This Special Issue comprises nine reviews offering perspectives from the development of neurodegeneration in different pathologies to neuronal protection, providing new views on the mechanism of neurodegeneration and associated processes and a summary of the progress in neuroscience. We hope you find these reviews interesting and informative and we thank the authors for these excellent contributions to The FEBS Journal.

ROCK inhibition in models of neurodegeneration and its potential for clinical translation.

Neurodegenerative disorders like Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis are affecting a rapidly increasing population worldwide. While common pathomechanisms such as protein aggregation, axonal degeneration, dysfunction of protein clearing and an altered immune response have been characterized, no disease-modifying therapies have been developed so far. Interestingly, a significant involvement of the Rho kinase (ROCK) signaling pathway has been described in all of these mechanisms making it a promising target for new therapeutic approaches. In this article, we first review current knowledge of the involvement of ROCK in neurodegenerative disorders and the utility of its inhibition as a disease-modifying therapy in different neurodegenerative disorders. After a detailed description of the biochemical characteristics of ROCK and its molecular interactors, differences of ROCK-expression under physiological and pathological conditions are compared. Next, different pharmacological and molecular-genetic strategies to inhibit ROCK-function are discussed, focusing on pharmacological ROCK-inhibitors. The role of the ROCK-pathway in cellular processes that are central in neurodegenerative disorders pathology like axonal degeneration, autophagy, synaptic and glial function is explained in detail. Finally, all available data on ROCK-inhibition in different animal models of neurodegenerative disorders is reviewed and first approaches for translation into human patients are discussed. Taken together, there is now extensive evidence from preclinical studies in several neurodegenerative disorders that characterize ROCK as a promising drug target for further translational research in neurodegenerative disorders.

Mouse models of neurodegenerative disease: preclinical imaging and neurovascular component.

Neurodegenerative diseases represent great challenges for basic science and clinical medicine because of their prevalence, pathologies, lack of mechanism-based treatments, and impacts on individuals. Translational research might contribute to the study of neurodegenerative diseases. The mouse has become a key model for studying disease mechanisms that might recapitulate in part some aspects of the corresponding human diseases. Neurodegenerative disorders are very complicated and multifactorial. This has to be taken in account when testing drugs. Most of the drugs screening in mice are very difficult to be interpretated and often useless. Mouse models could be condiderated a 'pathway models', rather than as models for the whole complicated construct that makes a human disease. Non-invasive in vivo imaging in mice has gained increasing interest in preclinical research in the last years thanks to the availability of high-resolution single-photon emission computed tomography (SPECT), positron emission tomography (PET), high field Magnetic resonance, Optical Imaging scanners and of highly specific contrast agents. Behavioral test are useful tool to characterize different animal models of neurodegenerative pathology. Furthermore, many authors have observed vascular pathological features associated to the different neurodegenerative disorders. Aim of this review is to focus on the different existing animal models of neurodegenerative disorders, describe behavioral tests and preclinical imaging techniques used for diagnose and describe the vascular pathological features associated to these diseases.

Tauroursodeoxycholic Acid Enhances Mitochondrial Biogenesis, Neural Stem Cell Pool, and Early Neurogenesis in Adult Rats.

Although neurogenesis occurs in restricted regions of the adult mammalian brain, neural stem cells (NSCs) produce very few neurons during ageing or after injury. We have recently discovered that the endogenous bile acid tauroursodeoxycholic acid (TUDCA), a strong inhibitor of mitochondrial apoptosis and a neuroprotective in animal models of neurodegenerative disorders, also enhances NSC proliferation, self-renewal, and neuronal conversion by improving mitochondrial integrity and function of NSCs. In the present study, we explore the effect of TUDCA on regulation of NSC fate in neurogenic niches, the subventricular zone (SVZ) of the lateral ventricles and the hippocampal dentate gyrus (DG), using rat postnatal neurospheres and adult rats exposed to the bile acid. TUDCA significantly induced NSC proliferation, self-renewal, and neural differentiation in the SVZ, without affecting DG-derived NSCs. More importantly, expression levels of mitochondrial biogenesis-related proteins and mitochondrial antioxidant responses were significantly increased by TUDCA in SVZ-derived NSCs. Finally, intracerebroventricular administration of TUDCA in adult rats markedly enhanced both NSC proliferation and early differentiation in SVZ regions, corroborating in vitro data. Collectively, our results highlight a potential novel role for TUDCA in neurologic disorders associated with SVZ niche deterioration and impaired neurogenesis.

Neuroprotective effects of erythropoietin on Alzheimer's dementia model in rats.

Although Alzheimer's disease (AD) is the most common age-related neurodegenerative disease and characterized by memory impairment, only symptomatic treatments are available. Because recombinant human erythropoietin (rhEPO) has various neuroprotective effects and improves cognitive function in animal models of neurodegenerative disorders, we investigated the therapeutic effects of rhEPO in an intracerebroventricular (ICV)-streptozotocin (STZ) animal model of sporadic-AD. A total of 24 Sprague-Dawley adult rats were divided into 4 groups of naive control (n = 6), sham-operated (n = 6), ICV-STZ + saline (n = 6) and ICV-STZ + rhEPO (n = 6). Twelve rats with Alzheimer's disease, induced by STZ injection (3 mg/kg) into both lateral ventricles using a stereotaxic frame (bilaterally ICV-STZ), were divided into 2 groups 5 days after the STZ injection: one treated with rhEPO 5000 (IU/kg/day, i.p.) and the other with 0.9% NaCl (1 mL/kg/day, i.p.) for 2 weeks. The sham-operated rats received bilaterally ICV-0.9% NaCl. No surgical operation or treatment was given to the naive-control animals. On day 20, a passive avoidance learning (PAL) test was used followed by sacrification and removal of the brain tissue in all animals. Brain TNF-α and ChAT levels were determined, and neurons in the hippocampal CA1 and CA3 regions were counted by Cresyl violet staining. ICV-STZ was found to significantly shorten the latency time on the PAL, increase brain TNF-α level, and decrease brain ChAT activity and the number of neurons in the hippocampal CA1 and CA3 regions. On the other hand, rhEPO significantly attenuated all these detrimental effects induced by STZ. RhEPO treatment significantly prevented the ICV-STZ-induced memory deficit by attenuating the hippocampal neuronal loss, neuroinflammation and cholinergic deficit in rats. This result suggests that rhEPO may be beneficial for treating AD.

Intracerebral interplay and neurotransmitter systems involvement in animal models of neurodegenerative disorders: EEG approach expectations.

Intracerebral interplay and neurotransmitter systems involvement in animal models of neurodegenerative disorders: EEG approach expectations.

Genetically modified pig models for neurodegenerative disorders

Increasing incidence of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease has become one of the most challenging health issues in ageing humans. One approach to combat this is to generate genetically modified animal models of neurodegenerative disorders for studying pathogenesis, prognosis, diagnosis, treatment, and prevention. Owing to the genetic, anatomic, physiologic, pathologic, and neurologic similarities between pigs and humans, genetically modified pig models of neurodegenerative disorders have been attractive large animal models to bridge the gap of preclinical investigations between rodents and humans. In this review, we provide a neuroanatomical overview in pigs and summarize and discuss the generation of genetically modified pig models of neurodegenerative disorders including Alzheimer's diseases, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, and ataxia-telangiectasia. We also highlight how non-invasive bioimaging technologies such as positron emission tomography (PET), computer tomography (CT), and magnetic resonance imaging (MRI), and behavioural testing have been applied to characterize neurodegenerative pig models. We further propose a multiplex genome editing and preterm recloning (MAP) approach by using the rapid growth of the ground-breaking precision genome editing technology CRISPR/Cas9 and somatic cell nuclear transfer (SCNT). With this approach, we hope to shorten the temporal requirement in generating multiple transgenic pigs, increase the survival rate of founder pigs, and generate genetically modified pigs that will more closely resemble the disease-causing mutations and recapitulate pathological features of human conditions.

Reduction of glutamate-induced excitotoxicity in murine primary neurons involving calpain inhibition

Excessive glutamate secretion leads to excitotoxicity, which has been shown to underlie neurodegenerative disorders. Excitotoxicity is in part exerted by overactivation of calpains, which promote neuronal cell death via induction of limited proteolysis of the cellular proteins p35, regulatory subunit of cyclin-dependent kinase 5, and αII-spectrin. We used primary murine neuronal cells in a model of glutamate toxicity. The protease inhibitor α1-antitrypsin was able to prevent glutamate toxicity as determined by MTT assay and immunofluorescence. Calpain and caspase 3 activity were reduced following α1-antitrypsin treatment, as assessed by calpain and caspase 3 activity assays. In addition we could observe a modulation of cleavage of the calpain/caspase substrates αII-spectrin and p35 in Western blots. In summary, α1-antitrypsin shows inhibitory effects on excitotoxicity of primary neurons involving the inhibition of calpain activity. The advantage of using α1-antitrypsin is that the substance is already in clinical use for the treatment of patients with hereditary α1-antitrypsin deficiency. Further experiments are required in animal models of neurodegenerative disorders to assess the suitability of this substance in patients suffering from Alzheimer's disease or Parkinson's disease.

Neuroprotective effects of an oxyntomodulin analogue in the MPTP mouse model of Parkinson's disease

Oxyntomodulin is a hormone and a growth factor. It activates two receptors, the Glucagon-like peptide 1 (GLP-1) and the glucagon receptor. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. These drugs have shown neuroprotective properties in animal models of neurodegenerative disorders. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in animal models of Parkinson's disease (PD), and a clinical trial in PD patients showed promising first positive results. d-Ser2-oxyntomodulin (Oxy) is a protease resistant oxyntomodulin analogue that has been developed to treat diabetes. Here we demonstrate for the first time that such analogues have neuroprotective effects. The drug showed protective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected daily (20mg/kg i.p.) for 7 days, and Oxy injected once-daily for 14 days i.p. Oxy treatment prevented or reversed the MPTP- induced motor impairment (Rotarod, spontaneous locomotion, swim activity, muscle strength test), the MPTP-induced reduction in Tyrosine Hydroxylase (TH) levels (dopamine synthesis) in the substantia nigra and basal ganglia, the reduction of the synaptic marker synapstophysin, the inactivation of the growth factor kinase Akt/PKB and of the anti-apoptotic signaling molecule Bcl-2, and the increase of levels of the pro-inflammatory cytokine TNF-α. The results demonstrate that oxyntomodulin analogues show promise as a novel treatment of PD.