Aspects Of Neuroprotection Research Articles

A critical appraisal on the involvement of plant-based extracts as neuroprotective agents (2012-2022): an effort to ease out decision-making process for researchers.

The purpose of this review study is to provide a condensed compilation of 164 medicinal plants that have been investigated for their neuroprotective aspects by researchers between the years 2012 and 2022 which also includes a recent update of 2023-2024. After using certain keywords to retrieve the data from SCOPUS, it was manually sorted to eliminate any instances of duplication. The article is streamlined into three major segments. The first segment takes a dig into the current global trend and attempts to decrypt vital information related to plant names, families, plant parts used, and neurological disorders investigated. The second segment of the article makes an attempt to present a comprehensive insight into the various mechanistic pathways through which phytochemicals can intervene to exert neuroprotection. The final segment of the manuscript is a bibliometric appraisal of all researches conducted. The study is based on 256 handpicked articles based on decided inclusion criteria. Illustrative compilation of various pathways citing their activation and deactivation channels are also presented with possible hitting points of various phytochemicals. The present study employed Microsoft Excel 2019 and VOS viewer as data visualisation tools.

Fluorinated apelin-13 mediates neuroprotective effects in multiple sclerosis models

Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease leading to demyelination and axonal loss. Current treatments are immunomodulatory or immunosuppressive drugs acting on the inflammatory component. However, these treatments do not adequately address the crucial aspect of neuroprotection. Recently, an association between an altered balance of adipokines and MS has been proposed as both a risk factor for developing MS and a chronic disease aggravating factor. Specifically, a decrease of apelin plasma levels in MS patients compared to controls correlates with the number of relapses and disease severity. Here we report a dramatic downregulation of apelin levels in the CNS of EAE mice which is also detected in MS patients brain samples compared to controls. Exploiting innovative design and synthesis techniques, we engineered a novel fluorinated apelin-13 peptide characterized by enhanced plasmatic stability compared to its native counterpart. With this peptide, we assessed the potential therapeutic benefits of apelin preventive supplementation in the EAE mouse model. We show that the fluorinated Apelin-13 peptide ameliorates EAE clinical score and preserves myelin content in the EAE MOG model recapitulating the progressive form of disease. These results combined with ex-vivo experiments in brain organotypic slices and in vitro studies in neurons and primary microglia and macrophages suggest that apelin has neuroprotective effects and influences the microglia/macrophages function.

Pterostilbene protects against H2 O2 -induced oxidative stress by regulating GAS6/Axl signaling in HL-1 cells.

Pterostilbene (PTE,trans-3,5-dimethoxy-4'-hydroxystilbene), a natural plant polyphenol, possesses numerous pharmacological effects, including antioxidant, antidiabetic, antiatherosclerotic, and neuroprotective aspects. This study aims to investigate whether PTE plays a protective role against oxidative stress injury by GAS6/Axlsignaling pathway in cardiomyocytes. Hydrogen peroxide (H2 O2 )-induced oxidative stress HL-1cells were used as models. The mechanism by which PTE protected oxidative stress is investigated by combining cell viability, cell ROS levels, apoptosis assay, molecular docking, quantitative real-time PCR, and western blot analysis. GAS6 shRNA was performed to investigate the involvement of GAS6/Axl pathways in PTE'sprotective role. The results showed that PTEtreatment improved the cell morphology and viability, and inhibited the apoptosis rate and ROS levels in H2 O2 -injured HL-1cells. Particularly, PTE treatment upregulated the levels of GAS6, Axl, and markers related to oxidative stress, apoptosis, and mitochondrial function related. Molecular docking showed that PTE and GAS6 have good binding ability. Taken together, PTE plays a protective role against oxidative stress injury through inhibiting oxidative stress and apoptosis and improving mitochondrial function. Particularly, GAS6/Axl axis is the surprisingly prominent in the PTE-mediated pleiotropic effects.

Enriched Environment Contributes to the Recovery from Neurotoxin-Induced Parkinson’s Disease Pathology

Parkinson’s disease (PD) is a neurological disorder that affects dopaminergic neurons. The lack of understanding of the underlying molecular mechanisms of PD pathology makes treating it a challenge. Several pieces of evidence support the protective role of enriched environment (EE) and exercise on dopaminergic neurons. The specific aspect(s) of neuroprotection after exposure to EE have not been identified. Therefore, we have investigated the protective role of EE on dopamine dysregulation and subsequent downregulation of DJ1 protein using in vitro and in vivo models of PD. Our study for the first time demonstrated that DJ1 expression has a direct correlation with dopamine downregulation in PD models and exposure to EE has a significant impact on improving the behavioral changes in PD mice. This research provides evidence that exercise in EE has a positive effect on PD without interfering with the current line of therapy.

Neuroprotective effect of hypoxic-hypercapnic training. Review

The neuroprotective effects of hypercapnia, especially with hypoxia combined, interested in the context of nerve cells forming protective mechanisms. Hypercapnia not only acts as a potent neuroprotector but also increases tissue tolerance to ischemia and reperfusion. Hypercapnic effects are based on many different mechanisms including energy metabolism modulation, adaptive signaling pathways activation, histological damage reduction, pro-inflammatory factors, angiogenesis activation, and activation of synthetic processes in neurons. The summarized data indicate prospects for further research to better understand the molecular and physiological aspects of neuroprotection during hypercapnia and hypoxia, as well as to determine the conditions under which the best neuroprotective effect is achieved with a subsequent reduction in neurological deficits. __________________________________________________________________________________________ Keywords: hypercapnia, hypoxia, neuroprotection, permissive hypercapnia, ischemia, stroke

Tanshinone-IIA mediated neuroprotection by modulating neuronal pathways.

The progression of neurological diseases is mainly attributed to oxidative stress, apoptosis, inflammation, and trauma, making them a primary public concern. Since no drugs can stop these neurological disorders from happening, active phytochemical intervention has been suggested as a possible treatment. Among the several phytochemicals being studied for their potential health advantages, tanshinone-IIA (Tan-IIA ) stands out due to its wide range of therapeuticeffects. Tan-IIA, derived from the Salvia miltiorrhiza plant, is a phenanthrenequinone. The pharmacological characteristics of Tan-IIAagainst various neurodegenerative and neuropsychiatric illnesses have led researchers to believe that the compound possesses neuroprotective potential. Tan-IIA has therapeutic potential in treating neurological diseases due to its capacity to cross the blood-brain barrier and its broad range of activities. In treating neurological disorders, Tan-IIA has been shown to have neuroprotective effects such as anti-apoptotic, anti-inflammatory, BBB protectant, and antioxidant properties. This article concisely summarises the latest scientific findings about the cellular and molecular aspects of Tan-IIA neuroprotection in relation to various neurological diseases. The results of preclinical studies on Tan-IIA provide insight into its potential application in future therapeutic development. This molecule rapidly establishes as a prominent bioactive compound for clinical research.

The modulation of potassium channels by estrogens facilitates neuroprotection.

Estrogens, the sex hormones, have the potential to govern multiple cellular functions, such as proliferation, apoptosis, differentiation, and homeostasis, and to exert numerous beneficial influences for the cardiovascular system, nervous system, and bones in genomic and/or non-genomic ways. Converging evidence indicates that estrogens serve a crucial role in counteracting neurodegeneration and ischemic injury; they are thereby being considered as a potent neuroprotectant for preventing neurological diseases such as Alzheimer's disease and stroke. The underlying mechanism of neuroprotective effects conferred by estrogens is thought to be complex and multifactorial, and it remains obscure. It is well established that the K+ channels broadly expressed in a variety of neural subtypes determine the essential physiological features of neuronal excitability, and dysfunction of these channels is closely associated with diverse brain deficits, such as ataxia and epilepsy. A growing body of evidence supports a neuroprotective role of K+ channels in malfunctions of nervous tissues, with the channels even being a therapeutic target in clinical trials. As multitarget steroid hormones, estrogens also regulate the activity of distinct K+ channels to generate varying biological actions, and accumulated data delineate that some aspects of estrogen-mediated neuroprotection may arise from the impact on multiple K+ channels, including Kv, BK, KATP, and K2P channels. The response of these K+ channels after acute or chronic exposure to estrogens may oppose pathological abnormality in nervous cells, which serves to extend our understanding of these phenomena.

The Multifaceted Role of Neuroprotective Plants in Alzheimer's Disease Treatment.

Alzheimer’s disease (AD) is an age-related, progressive neurodegenerative disorder characterized by impaired cognition, memory loss, and altered personality. Many of the available pharmaceutical treatments do not alter the onset of disease progression. Recently, alternatives to developed drug candidates have been explored including medicinal plants and herbal treatments for the treatment of AD. This article examines the role of herbal plant extracts and the neuroprotective effects as alternative modes of intervention for AD progression. These extracts contain key metabolites that culminate alterations in AD progression. The traditional plant extracts explored in this article induce a variety of beneficial properties, including antioxidants, anti-inflammatory, and enhanced cognition, while also inducing activity on AD drug targets such as Aβ degradation. While these neuroprotective aspects for AD are relatively recent, there is great potential in the drug discovery aspect of these plant extracts for future use in AD treatment.

Scopoletin: a review of its source, biosynthesis, methods of extraction, and pharmacological activities.

Scopoletin, also known as 6-methoxy-7 hydroxycoumarin, is one of the naturally occurring coumarin commonly found in many edible plants and plays an important role in human health. Despite the various potential pharmacological properties, the biosynthesis process, method of extraction, and mechanism of action on this compound have not been documented well. In this current review, the biosynthesis pathway, distribution of scopoletin in the plant kingdom, and extraction techniques are elaborated. The in vitro, in vivo, and in silico pharmacological studies are also discussed on antioxidant, antimicrobial, anticancer, anti-inflammation, and neuroprotective aspects of scopoletin. This study may help to understand the benefit of scopoletin containing plants and would be beneficial for the prevention and treatment of diseases.

Assessing therapeutic potential of PLD1 inhibition in dementia: Systematic assessment of behavior, electrophysiology & mechanisms of synaptic dysfunction using different parameters including sex‐specific differences

AbstractBackgroundPhosphatidyl choline phospholipase D (PC‐PLD), a lipolytic enzyme that breaks down membrane phospholipids via two isoforms ‐ a constitutively expressed PLD2 and an inducible PLD1 isoform ‐ are also involved in developmentally important signaling mechanisms that regulate synaptic function. We were the first to propose and present a systematic study that established PLD1 as the aberrantly elevated isoform in AD and related dementia using human clinical samples and provided functional proof using mouse models to demonstrate the underlying synaptic dysfunction and memory deficits.MethodsWe used different transgenic rodent models of AD‐like pathology and did a corroborative assessment of behavior, electrophysiology and biochemistry including western blots analysis, Golgi studies and immunofluorescence to assess the efficacy of treatment of the aberrantly elevated PLD1 levels using chronic regimen of a specific small molecule inhibitor.ResultChronic PLD1 inhibition is effective in ameliorating the synaptic dysfunction and associated memory deficits in the treated cohort compared to the age‐matched cohort. We also assessed and report sex‐specific changes in these responses that strengthen our understanding of the underlying mechanisms and brain regions that are targeted by the therapeutic approaches.ConclusionUsing chronic administration of a well‐tolerated halopemide derivative of the specific PLD1 isoform inhibitor in the preclinical mouse models of synaptic dysfunction and memory deficits associated with amyloidogenic effects of Aβ and tau, we demonstrated neuroprotective aspects involving changes in the dendritic spine integrity that contributes to the preservation of memory with an emphasis on the sex‐specific effects.

Specific small-molecule inhibition of PLD1 prevents ADRD-like memory deficits by preserving dendritic spine integrity driven by amyloidogenic proteins.

Phosphatidyl choline phospholipase D (PC-PLD), a lipolytic enzyme that breaks down membrane phospholipids via two isoforms - a constitutively expressed PLD2 and an inducible PLD1 isoform - are also involved in developmentally important signaling mechanisms that regulate synaptic function. We were the first to propose and present a systematic study that established PLD1 as the aberrantly elevated isoform in AD and related dementia using human clinical samples and provided functional proof using mouse models to demonstrate the underlying synaptic dysfunction and memory deficits. Synaptosomal Western blot analysis on 12 month 3xTg-AD mice hippocampi were used to investigate neuronal PLD1 expression and function. Long term potentiation of PLD1 dependent changes using pharmacological approaches in ex vivo slice preparations from wildtype and transgenic mouse models were used to assess synaptic perturbations that were first studied using the novel object recognition memory (NOR) and fear conditioning (FC) paradigms. Chronic PLD1 small molecule inhibitor treatment was assessed to ascertain the efficacy against Aβ and tau-driven AD-like memory deficit progression. Lastly, brain tissues from these animals were subjected to Western Blot analyses, Golgi analysis, immunohistochemical analysis to ascertain the potential signaling mechanism(s) that is/are perturbed/altered by overexpression of PLD1 in such diseased states. Chronic PLD1 inhibition ameliorates the synaptic dysfunction and underlying memory deficits in the 3xTg-AD mouse model by specific action on preserving mushroom spine dendritic spine integrity. Further analysis using Western Blots revealed an underlying mechanism. Using chronic administration of a well-tolerated halopemide derivative of the specific PLD1 isoform inhibitor in the preclinical mouse models of synaptic dysfunction and memory deficits associated with amyloidogenic effects of Aβ and tau, we demonstrated neuroprotective aspects involving changes in the dendritic spine integrity that contributes to the preservation of memory.

LC-MS/MS for Ultra-Sensitive Quantification of Multiple Estrogens in the Blood and Brain

Estrogens are steroid hormones that affect many aspects of brain function, including cognition, social behavior, and neuroprotection. It is well-known that estrogens are synthesized in the ovaries. Estrogens are also synthesized in the brain, where aromatase is expressed in specific regions. Importantly, estrogens play crucial roles in the brain, even at extremely low levels. Current assays lack the necessary sensitivity and/or specificity to measure brain-synthesized estrogens. Furthermore, current methods focus on only 17β-estradiol and generally disregard other estrogens that are synthesized in the brain. Here, we developed a method to measure several estrogens simultaneously, with high sensitivity and specificity. To improve sensitivity, we derivatized estrogens with 1,2-dimethylimidazole-5-sulfonyl-chloride (DMIS). We used liquid chromatography tandem mass spectrometry (LC-MS/MS) to examine a panel of eight estrogens: 17β-estradiol, 17α-estradiol, estrone, estriol, 2-hydroxyestradiol, 4-hydroxyestradiol, 2-methoxyestradiol, and 4-methoxyestradiol. After derivatization, we have improved sensitivity 20-fold, detecting as little as 0.01 pg per sample, demonstrating that our method is extremely sensitive. For each analyte, we have identified a distinct retention time as well as 2 scheduled multiple reaction monitoring (sMRM) transitions that were used as quality control criteria for clear identification. Therefore, we are able to distinguish each estrogen (even stereoisomers) by the chromatographic separation and the sMRM, demonstrating that our method is highly specific.This method has been applied to microdissected brain samples. Initially, we used a songbird model because songbirds have high levels of aromatase and 17β-estradiol in specific brain regions. We were able to simultaneously quantify multiple estrogens in small amounts of brain sample (1-2 mg). We examined seasonal changes of estrogens in the brain and blood. Future work will apply this method to mouse, rat, and human samples and expand the panel of estrogens examined. Our ultra-sensitive assay is essential for small animal models, where estrogen measurement is extremely challenging because of the limited amount of brain tissue. This novel technique will also have wide-ranging applications for basic research and clinical testing, including estrogen measurement in humans with low estrogen levels, such as men, pre-pubertal children, and post-menopausal women.

Predicting a Potential Link to Antidepressant Effect: Neuroprotection of Zhi-zi-chi Decoction on Glutamate-induced Cytotoxicity in PC12 Cells.

Zhi-zi-chi Decoction (ZZCD), composed of Fructus Gardeniae (Zhizi in Chinese, ZZ in brief) and Semen sojae praeparatum (Dandouchi in Chinese, DDC in brief), has been used as a drug therapy for depression for thousands of years in China. However, the antidepressant mechanism of ZZCD still remains unknown. This study was aimed at exploring antidepressant effects of ZZCD from the aspect of neuroprotection based on herb compatibility. Glutamate-treated PC12 cells and chronic unpredictable mild stress (CUMS)-induced rats were established as models of depression in vitro and in vivo respectively. Cell viability, lactate dehydrogenase (LDH), apoptosis rate, reactive oxygen species (ROS), glutathione reductase (GR) and superoxide dismutase (SOD), and the expressions of Bax, Bcl-2 and cyclic adenosine monophosphate-response element binding protein (CREB) were measured to compare neuroprotection among single herbs and the formula in vitro. Behavior tests were conducted to validate antidepressant effects of ZZCD in vivo. Results showed that the compatibility of ZZ and DDC increased cell viability and activities of GR and SOD, and decreased the levels of LDH, apoptosis cells and ROS. Besides, the expressions of Bcl-2 and CREB were up-regulated while that of Bax was down-regulated by ZZCD. Furthermore, the compatibility of ZZ and DDC reversed abnormal behaviors in CUMS-induced rats and displayed higher efficacy than any of the single herbs. This study revealed that the antidepressant effects of ZZCD were closely associated with neuroprotection and elucidated synergistic effects of the compatibility of ZZ and DDC based on it.

Pathogenic and protective roles of extracellular vesicles in neurodegenerative diseases.

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and polyglutamine diseases are caused by aggregation and abnormal accumulation of the disease-causative proteins in brain and spinal cord. Recent studies have suggested that proteins associated with neurodegenerative diseases are secreted and transmitted intercellularly via extracellular vesicles (EVs), which may be involved in propagation of abnormal protein accumulation and progressive degeneration in patient brains. On the other hand, it has been also reported that EVs have neuroprotective roles in these diseases, which potentially contribute to preventing aggregation formation and aberrant accumulation of the disease-associated proteins. In this review, I summarize the current understanding of the roles of EVs in neurodegenerative diseases, especially focussing on the pathogenic and neuroprotective aspects. Elucidation of these two aspects of EVs would provide insight into not only potential therapeutic targets for treatment of neurodegenerative diseases but also development of EV-based biomarkers for disease diagnostics.

Temporal evolution of heme oxygenase-1 expression in reactive astrocytes and microglia in response to traumatic brain injury

Heme oxygenase-1 (HO-1) is an inducible enzyme that catabolizes heme into biliverdin (which is converted to bilirubin), carbon monoxide, and free iron. HO-1 and its downstream molecules have antioxidant and anti-inflammatory functions, making the effects of HO-1 difficult to predict. It is unknown if HO-1 expression has neuroprotective or neurodegenerative sequelae after traumatic brain injury (TBI). In adult male mice, we quantitatively investigated HO-1 expression in reactive astrocytes and microglia in a controlled cortical impact (CCI) model of TBI at 1, 7, 14, and 30 days post-injury (dpi). Immunoglobulin G (IgG) staining for blood-brain barrier (BBB) permeability was significantly increased at 1 and 7 dpi in TBI mice compared to controls. HO-1 expression in astrocytes was significantly increased acutely and sub-acutely (1, 7, 14 dpi) compared to controls. Significantly elevated expression of HO-1 in microglia was only observed at 14 and 30 dpi relative to controls. HO-1 expression remained elevated at 30 dpi following TBI relative to controls. This study for the first time demonstrates that HO-1 is highly expressed in perilesional tissues after TBI, but primarily in cells that contribute to the neuroinflammatory response. Modulating HO-1 expression may provide a path to therapeutic intervention by enhancing the neuroprotective aspects of HO-1. Summary statement:Heme oxygenase-1 expression after traumatic brain injury in adult male mice occurs first in reactive astrocytes followed by dramatic increases in microglia adjacent to the injury site.

Neuroprotective Aspects of Cannabinoid Compounds

The accumulation of reliable data on the effects of cannabinoids is essential for understanding their possible beneficial effects on the central nervous system (CNS). Investigating individual substances along with the action of different combinations may show new possibilities for cannabinoids as neuroprotective agents. The data collected so far reveals the complexity of the mechanism of cannabinoids action on CNS, and even more complex and poorly understood are the effects when combined. Moreover, combining cannabinoids with different drugs and chemicals may lead to a decrease in beneficial effects. These characteristics of their action emphasize the complexity of the molecular mechanisms of neuroprotection and the lack of reliable information that may contribute to the safe and effective use of cannabinoids as medicines with valuable neuroprotective properties. The current brief review summarizes present data related to the protective effects of some cannabinoids on CNS and possible mechanisms involved in cannabinoid-mediated neuroprotection.

Neuroprotection mediated by natural products and their chemical derivatives.

Neuronal injuries can lead to various diseases such as neurodegenerative diseases, stroke, trauma, ischemia and, more specifically, glaucoma and optic neuritis. The cellular mechanisms that regulate neuronal death include calcium influx and calcium overload, excitatory amino acid release, oxidative stress, inflammation and microglial activation. Much attention has been paid to the effective prevention and treatment of neuroprotective drugs by natural products. This review summarizes the neuroprotective aspects of natural products, extracted from Panax ginseng, Camellia sinensis, soy and some other plants, and some of their chemical derivatives. Their antioxidative and anti-inflammatory action and their inhibition of apoptosis and microglial activation are assessed. This will provide new directions for the development of novel drugs and strategies to treat neurodegenerative diseases.

Microscopic Viscosity of Neuronal Plasma Membranes Measured Using Fluorescent Molecular Rotors: Effects of Oxidative Stress and Neuroprotection.

Molecular mobility in neuronal plasma membranes is a crucial factor in brain function. Microscopic viscosity is an important parameter that determines molecular mobility. This study presents the first direct measurement of the microviscosity of plasma membranes of live neurons. Microviscosity maps were obtained using fluorescence lifetime imaging of environment-sensing dyes termed "molecular rotors". Neurons were investigated both in the basal state and following common neurodegenerative stimuli, excitotoxicity, or oxidative stress. Both types of neurotoxic challenges induced microviscosity decrease in cultured neurons, and oxidant-induced membrane fluidification was counteracted by the wide-spectrum neuroprotectant, the H3 peptide. These results provide new insights into molecular mobility in neuronal membranes, paramount for basic brain function, and suggest that preservation of membrane stability may be an important aspect of neuroprotection in brain insults and neurodegenerative disorders.

Transcriptome Analysis Reveals Neuroprotective aspects of Human Reactive Astrocytes induced by Interleukin 1\u03b2

Reactive astrogliosis is a critical process in neuropathological conditions and neurotrauma. Although it has been suggested that it confers neuroprotective effects, the exact genomic mechanism has not been explored. The prevailing dogma of the role of astrogliosis in inhibition of axonal regeneration has been challenged by recent findings in rodent model’s spinal cord injury, demonstrating its neuroprotection and axonal regeneration properties. We examined whether their neuroprotective and axonal regeneration potentials can be identify in human spinal cord reactive astrocytes in vitro. Here, reactive astrogliosis was induced with IL1β. Within 24 hours of IL1β induction, astrocytes acquired reactive characteristics. Transcriptome analysis of over 40000 transcripts of genes and analysis with PFSnet subnetwork revealed upregulation of chemokines and axonal permissive factors including FGF2, BDNF, and NGF. In addition, most genes regulating axonal inhibitory molecules, including ROBO1 and ROBO2 were downregulated. There was no increase in the gene expression of “Chondroitin Sulfate Proteoglycans” (CSPGs’) clusters. This suggests that reactive astrocytes may not be the main CSPG contributory factor in glial scar. PFSnet analysis also indicated an upregulation of “Axonal Guidance Signaling” pathway. Our result suggests that human spinal cord reactive astrocytes is potentially neuroprotective at an early onset of reactive astrogliosis.

CD24 expression does not affect dopamine neuronal survival in a mouse model of Parkinson's disease.

Parkinson’s disease (PD) is a progressive neurodegenerative condition that is characterised by the loss of specific populations of neurons in the brain. The mechanisms underlying this selective cell death are unknown but by using laser capture microdissection, the glycoprotein, CD24 has been identified as a potential marker of the populations of cells that are affected in PD. Using in situ hybridization and immunohistochemistry on sections of mouse brain, we confirmed that CD24 is robustly expressed by many of these subsets of cells. To determine if CD24 may have a functional role in PD, we modelled the dopamine cell loss of PD in Cd24 mutant mice using striatal delivery of the neurotoxin 6-OHDA. We found that Cd24 mutant mice have an anatomically normal dopamine system and that this glycoprotein does not modulate the lesion effects of 6-OHDA delivered into the striatum. We then undertook in situ hybridization studies on sections of human brain and found—as in the mouse brain—that CD24 is expressed by many of the subsets of the cells that are vulnerable in PD, but not those of the midbrain dopamine system. Finally, we sought to determine if CD24 is required for the neuroprotective effect of Glial cell-derived neurotrophic factor (GDNF) on the dopaminergic nigrostriatal pathway. Our results indicate that in the absence of CD24, there is a reduction in the protective effects of GDNF on the dopaminergic fibres in the striatum, but no difference in the survival of the cell bodies in the midbrain. While we found no obvious role for CD24 in the normal development and maintenance of the dopaminergic nigrostriatal system in mice, it may have a role in mediating the neuroprotective aspects of GDNF in this system.