International Review Of Neurobiology[JOURNAL]
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200 papers
The adenosine A receptor in the basal ganglia: Expression, heteromerization, functional selectivity and signalling.
Franco R, Navarro G, Martínez-Pinilla E
Int Rev Neurobiol · 2023 · PMID 37741696 · Publisher ↗
Adenosine is a neuroregulatory nucleoside that acts through four G protein-coupled receptors (GPCRs), A, A, A and A, which are widely expressed in cells of the nervous system. The A receptor (AR), the GPCR with the highe...
Adenosine is a neuroregulatory nucleoside that acts through four G protein-coupled receptors (GPCRs), A, A, A and A, which are widely expressed in cells of the nervous system. The A receptor (AR), the GPCR with the highest expression in the striatum, has a similar role to that of receptors for dopamine, one of the main neurotransmitters. Neuronal and glial ARs participate in the modulation of dopaminergic transmission and act in almost any action in which the basal ganglia is involved. This chapter revisits the expression of the AR in the basal ganglia in health and disease, and describes the diversity of signalling depending on whether the receptors are expressed as monomer or as heteromer. The AR can interact with other receptors as adenosine A, dopamine D, or cannabinoid CB to form heteromers with relevant functions in the basal ganglia. Heteromerization, with these and other GPCRs, provides diversity to AR-mediated signalling and to the modulation of neurotransmission. Thus, selective AR antagonists have neuroprotective potential acting directly on neurons, but also through modulation of glial cell activation, for example, by decreasing neuroinflammatory events that accompany neurodegenerative diseases. In fact, AR antagonists are safe and their potential in the therapy of Parkinson's disease has already led to the approval of one of them, istradefylline, in Japan and United States. The receptor also has a key role in reward circuits and, again, heteromers with dopamine receptors, but also with cannabinoid CB receptors, participate in the events triggered by drugs of abuse.
Adenosine A receptor and glia.
Gao Z
Int Rev Neurobiol · 2023 · PMID 37741695 · Publisher ↗
The adenosine A receptor (AR) is abundantly expressed in the brain, including both neurons and glial cells. While the expression of AR is relative low in glia, its levels elevate robustly in astrocytes and microglia unde...
The adenosine A receptor (AR) is abundantly expressed in the brain, including both neurons and glial cells. While the expression of AR is relative low in glia, its levels elevate robustly in astrocytes and microglia under pathological conditions. Elevated AR appears to play a detrimental role in a number of disease states, by promoting neuroinflammation and astrocytic reaction to contribute to the progression of neurodegenerative and psychiatric diseases.
Chemobrain: An accelerated aging process linking adenosine A receptor signaling in cancer survivors.
Oliveros A, Poleschuk M, Cole PD … +2 more , Boison D, Jang MH
Int Rev Neurobiol · 2023 · PMID 37741694 · Full text
Chemotherapy has a significant positive impact in cancer treatment outcomes, reducing recurrence and mortality. However, many cancer surviving children and adults suffer from aberrant chemotherapy neurotoxic effects on l...
Chemotherapy has a significant positive impact in cancer treatment outcomes, reducing recurrence and mortality. However, many cancer surviving children and adults suffer from aberrant chemotherapy neurotoxic effects on learning, memory, attention, executive functioning, and processing speed. This chemotherapy-induced cognitive impairment (CICI) is referred to as "chemobrain" or "chemofog". While the underlying mechanisms mediating CICI are still unclear, there is strong evidence that chemotherapy accelerates the biological aging process, manifesting as effects which include telomere shortening, epigenetic dysregulation, oxidative stress, mitochondrial defects, impaired neurogenesis, and neuroinflammation, all of which are known to contribute to increased anxiety and neurocognitive decline. Despite the increased prevalence of CICI, there exists a lack of mechanistic understanding by which chemotherapy detrimentally affects cognition in cancer survivors. Moreover, there are no approved therapeutic interventions for this condition. To address this gap in knowledge, this review attempts to identify how adenosine signaling, particularly through the adenosine A receptor, can be an essential tool to attenuate accelerated aging phenotypes. Importantly, the adenosine A receptor uniquely stands at the crossroads of cancer treatment and improved cognition, given that it is widely known to control tumor induced immunosuppression in the tumor microenvironment, while also posited to be an essential regulator of cognition in neurodegenerative disease. Consequently, we propose that the adenosine A receptor may provide a multifaceted therapeutic strategy to enhance anticancer activity, while combating chemotherapy induced cognitive deficits, both which are essential to provide novel therapeutic interventions against accelerated aging in cancer survivors.
AR and traumatic brain injury.
Zhao Y, Ning YL, Zhou YG
Int Rev Neurobiol · 2023 · PMID 37741693 · Publisher ↗
Accumulating evidence has revealed the adenosine 2A receptor is a key tuner for neuropathological and neurobehavioral changes following traumatic brain injury by experimental animal models and a few clinical trials. Here...
Accumulating evidence has revealed the adenosine 2A receptor is a key tuner for neuropathological and neurobehavioral changes following traumatic brain injury by experimental animal models and a few clinical trials. Here, we highlight recent data involving acute/sub-acute and chronic alterations of adenosine and adenosine 2A receptor-associated signaling in pathological conditions after trauma, with an emphasis of traumatic brain injury, including neuroinflammation, cognitive and psychiatric disorders, and other severe consequences. We expect this would lead to the development of therapeutic strategies for trauma-related disorders with novel mechanisms of action.
AR antagonist treatment for multiple sclerosis: Current progress and future prospects.
Qi C, Feng Y, Jiang Y … +4 more , Chen W, Vakal S, Chen JF, Zheng W
Int Rev Neurobiol · 2023 · PMID 37741692 · Publisher ↗
Emerging evidence suggests that both selective and non-selective Adenosine A receptor (AR) antagonists could effectively protect mice from experimental autoimmune encephalomyelitis (EAE), which is the most commonly used...
Emerging evidence suggests that both selective and non-selective Adenosine A receptor (AR) antagonists could effectively protect mice from experimental autoimmune encephalomyelitis (EAE), which is the most commonly used animal model for multiple sclerosis (MS) research. Meanwhile, the recent FDA approval of Nourianz® (istradefylline) in 2019 as an add-on treatment to levodopa in Parkinson's disease (PD) with "OFF" episodes, along with its proven clinical safety, has prompted us to explore the potential of AR antagonists in treating multiple sclerosis (MS) through clinical trials. However, despite promising findings in experimental autoimmune encephalomyelitis (EAE), the complex and contradictory role of AR signaling in EAE pathology has raised concerns about the feasibility of using AR antagonists as a therapeutic approach for MS. This review addresses the potential effect of AR antagonists on EAE/MS in both the peripheral immune system (PIS) and the central nervous system (CNS). In brief, AR antagonists had a moderate effect on the proliferation and inflammatory response, while exhibiting a potent anti-inflammatory effect in the CNS through their impact on microglia, astrocytes, and the endothelial cells/epithelium of the blood-brain barrier. Consequently, AR signaling remains an essential immunomodulator in EAE/MS, suggesting that AR antagonists hold promise as a drug class for treating MS.
Adenosine A signals and dystonia.
Takahashi M
Int Rev Neurobiol · 2023 · PMID 37741691 · Publisher ↗
Dystonia is a movement disorder characterized by sustained or intermittent involuntary muscle contractions, which is also seen in an advanced stage of Parkinson's disease (PD) as camptocormia, torticollis, and Pisa syndr...
Dystonia is a movement disorder characterized by sustained or intermittent involuntary muscle contractions, which is also seen in an advanced stage of Parkinson's disease (PD) as camptocormia, torticollis, and Pisa syndrome. Istradefylline, an adenosine A receptor antagonist, can be used for the treatment of PD to reduce 'off'-time period, and several clinical studies demonstrated the improvement of camptocormia, which have many similar features to dopa-responsive/non-responsive dystonia. Many animal models of dystonia showed that adenosine A receptor colocalized with dopamine D2 positive spiny projection neurons in indirect pathway of basal ganglia circuit, and also in the cholinergic interneurons that affects the balance of indirect and direct pathway of basal ganglia. In this chapter, the potential effect of adenosine A antagonism on dystonia was discussed in view of clinical studies of PD with postural abnormalities and the findings of dystonia mouse models.
Adenosine A receptors and sleep.
Korkutata M, Lazarus M
Int Rev Neurobiol · 2023 · PMID 37741690 · Publisher ↗
Adenosine, a known endogenous somnogen, induces sleep via A and A receptors. In this chapter, we review the current knowledge regarding the role of the adenosine A receptor and its agonists, antagonists, and allosteric m...
Adenosine, a known endogenous somnogen, induces sleep via A and A receptors. In this chapter, we review the current knowledge regarding the role of the adenosine A receptor and its agonists, antagonists, and allosteric modulators in sleep-wake regulation. Although many adenosine A receptor agonists, antagonists, and allosteric modulators have been identified, only a few have been tested to see if they can promote sleep or wakefulness. In addition, the growing popularity of natural sleep aids has led to an investigation of natural compounds that may improve sleep by activating the adenosine A receptor. Finally, we discuss the potential therapeutic advantage of allosteric modulators of adenosine A receptors over classic agonists and antagonists for treating sleep and neurologic disorders.
Effects of adenosine A receptors on cognitive function in health and disease.
Garcia CP, Licht-Murava A, Orr AG
Int Rev Neurobiol · 2023 · PMID 37741689 · Publisher ↗
Adenosine A receptors have been studied extensively in the context of motor function and movement disorders such as Parkinson's disease. In addition to these roles, A receptors have also been increasingly implicated in c...
Adenosine A receptors have been studied extensively in the context of motor function and movement disorders such as Parkinson's disease. In addition to these roles, A receptors have also been increasingly implicated in cognitive function and cognitive impairments in diverse conditions, including Alzheimer's disease, schizophrenia, acute brain injury, and stress. We review the roles of A receptors in cognitive processes in health and disease, focusing primarily on the effects of reducing or enhancing A expression levels or activities in animal models. Studies reveal that A receptors in neurons and astrocytes modulate multiple aspects of cognitive function, including memory and motivation. Converging evidence also indicates that A receptor levels and activities are aberrantly increased in aging, acute brain injury, and chronic disorders, and these increases contribute to neurocognitive impairments. Therapeutically targeting A receptors with selective modulators may alleviate cognitive deficits in diverse neurological and neuropsychiatric conditions. Further research on the exact neural mechanisms of these effects as well as the efficacy of selective A modulators on cognitive alterations in humans are important areas for future investigation.
Adenosine A antagonists and Parkinson's disease.
Offit M, Nagle B, Ozay G … +4 more , Zhang I, Kerasidis A, Torres-Yaghi Y, Pagan F
Int Rev Neurobiol · 2023 · PMID 37741688 · Publisher ↗
Although there is no cure for Parkinson's disease (PD), there are several classes of medications with various mechanisms of action that can help improve the functionality of someone with PD. Dopamine derivatives are firs...
Although there is no cure for Parkinson's disease (PD), there are several classes of medications with various mechanisms of action that can help improve the functionality of someone with PD. Dopamine derivatives are first line therapies for PD, hence dopamine receptor agonists (DAs) have been shown to improve functionality of symptoms in PD patients. The two main formulations of dopamine agonist medications in PD therapy are ergoline and non-ergoline derivatives. Additionally, it has been shown that PD can involve irregularities in other neurotransmitters, such as acetylcholine, norepinephrine, and serotonin, hence why non-dopaminergic medications are also vital in PD management. Examples include NMDA receptor antagonists, dopamine antagonists (i.e. neuroleptics), acetylcholine receptor antagonists, serotonin receptor 2A agonists, and adenosine A antagonists. In general, dopaminergic medications are the most effective in improving motor involvement with PD, whereas non-dopaminergic medications tend to focus on the non-motor involvement of PD. In this chapter, we will focus on the chemistry and medication background on dopaminergic vs non-dopaminergic therapy, with a focus of adenosine A antagonists at the end.
A adenosine receptor agonists, antagonists, inverse agonists and partial agonists.
Jacobson KA, Suresh RR, Oliva P
Int Rev Neurobiol · 2023 · PMID 37741687 · Full text
The Gs-coupled A adenosine receptor (AAR) has been explored extensively as a pharmaceutical target, which has led to numerous clinical trials. However, only one selective AAR agonist (regadenoson, Lexiscan) and one selec...
The Gs-coupled A adenosine receptor (AAR) has been explored extensively as a pharmaceutical target, which has led to numerous clinical trials. However, only one selective AAR agonist (regadenoson, Lexiscan) and one selective AAR antagonist (istradefylline, Nouriast) have been approved by the FDA, as a pharmacological agent for myocardial perfusion imaging (MPI) and as a cotherapy for Parkinson's disease (PD), respectively. Adenosine is widely used in MPI, as Adenoscan. Despite numerous unsuccessful clinical trials, medicinal chemical activity around AAR ligands has accelerated recently, particularly through structure-based drug design. New drug-like AAR antagonists for PD and cancer immunotherapy have been identified, and many clinical trials have ensued. For example, imaradenant (AZD4635), a compound that was designed computationally, based on AAR X-ray structures and biophysical mapping. Mixed AAR/AAR antagonists are also hopeful for cancer treatment. AAR antagonists may also have potential as neuroprotective agents for treatment of Alzheimer's disease.
Dystonia genes and their biological pathways.
Di Fonzo A, Jinnah HA, Zech M
Int Rev Neurobiol · 2023 · PMID 37482402 · Publisher ↗
High-throughput sequencing has been instrumental in uncovering the spectrum of pathogenic genetic alterations that contribute to the etiology of dystonia. Despite the immense heterogeneity in monogenic causes, studies pe...
High-throughput sequencing has been instrumental in uncovering the spectrum of pathogenic genetic alterations that contribute to the etiology of dystonia. Despite the immense heterogeneity in monogenic causes, studies performed during the past few years have highlighted that many rare deleterious variants associated with dystonic presentations affect genes that have roles in certain conserved pathways in neural physiology. These various gene mutations that appear to converge towards the disruption of interconnected cellular networks were shown to produce a wide range of different dystonic disease phenotypes, including isolated and combined dystonias as well as numerous clinically complex, often neurodevelopmental disorder-related conditions that can manifest with dystonic features in the context of multisystem disturbances. In this chapter, we summarize the manifold dystonia-gene relationships based on their association with a discrete number of unifying pathophysiological mechanisms and molecular cascade abnormalities. The themes on which we focus comprise dopamine signaling, heavy metal accumulation and calcifications in the brain, nuclear envelope function and stress response, gene transcription control, energy homeostasis, lysosomal trafficking, calcium and ion channel-mediated signaling, synaptic transmission beyond dopamine pathways, extra- and intracellular structural organization, and protein synthesis and degradation. Enhancing knowledge about the concept of shared etiological pathways in the pathogenesis of dystonia will motivate clinicians and researchers to find more efficacious treatments that allow to reverse pathologies in patient-specific core molecular networks and connected multipathway loops.
What have we learned about the biology of dystonia from deep brain stimulation?
Marie V
Int Rev Neurobiol · 2023 · PMID 37482401 · Publisher ↗
Deep brain stimulation has dramatically changed the management of patients with dystonia, therapeutic approach of dystonia with marked improvement of dystonia and functional disability. However, despite decades of experi...
Deep brain stimulation has dramatically changed the management of patients with dystonia, therapeutic approach of dystonia with marked improvement of dystonia and functional disability. However, despite decades of experience and identification of good prognosis factors, prediction of beneficial effect at the individual level is still a challenge. There is inter-individual variability in therapeutic outcome. Genetic factors are identified but subgroups of patients still have relapse or worsening of dystonia in short or long term. Possible "biological factors" underlying such a difference among patients are discussed, including structural or functional differences including altered plasticity.
How does botulinum toxin really work?
Belvisi D, Leodori G, Costanzo M … +2 more , Conte A, Berardelli A
Int Rev Neurobiol · 2023 · PMID 37482400 · Publisher ↗
Over the past 30 years, Botulinum toxin (BoNT) has emerged as an effective and safe therapeutic tool for a number of neurological conditions, including dystonia. To date, the exact mechanism of action of BoNT in dystonia...
Over the past 30 years, Botulinum toxin (BoNT) has emerged as an effective and safe therapeutic tool for a number of neurological conditions, including dystonia. To date, the exact mechanism of action of BoNT in dystonia is not fully understood. Although it is well known that BoNT mainly acts on the neuromuscular junction, a growing body of evidence suggests that the therapeutic effect of BoNT in dystonia may also depend on its ability to modulate peripheral sensory feedback from muscle spindles. Animal models also suggest a retrograde and anterograde BoNT transportation from the site of injection to central nervous system structures. In humans, however, BoNT central effects seem to depend on the modulation of afferent input rather than on BoNT transportation. In this chapter, we aimed to report and discuss research evidence providing information on the possible mechanisms of action of BoNT in relation to treatment of dystonia.
Dystonia and tremor: Do they have a shared biology?
Lenka A, Pandey S
Int Rev Neurobiol · 2023 · PMID 37482399 · Publisher ↗
Dystonia and tremor are the two most commonly encountered hyperkinetic movement disorders encountered in clinical practice. While there has been substantial progress in the research on these two disorders, there also exi...
Dystonia and tremor are the two most commonly encountered hyperkinetic movement disorders encountered in clinical practice. While there has been substantial progress in the research on these two disorders, there also exists a lot of gray areas. Entities such as dystonic tremor and tremor associated with dystonia occupy a major portion of the "gray zone". In addition, there is a marked clinical heterogeneity and overlap of several clinical and epidemiological features among dystonia and tremor. These facts raise the possibility that dystonia and tremor could be having shared biology. In this chapter, we revisit critical aspects of this possibility that may have important clinical and research implications in the future. We comprehensively review the points in favor and against the theory that dystonia and tremor have shared biology from clinical, epidemiological, genetic and neuroimaging studies.
Dystonia and Parkinson's disease: Do they have a shared biology?
Matar E, Bhatia K
Int Rev Neurobiol · 2023 · PMID 37482398 · Publisher ↗
Parkinsonism and dystonia co-occur across many movement disorders and are most encountered in the setting of Parkinson's disease. Here we aim to explore the shared neurobiological underpinnings of dystonia and parkinsoni...
Parkinsonism and dystonia co-occur across many movement disorders and are most encountered in the setting of Parkinson's disease. Here we aim to explore the shared neurobiological underpinnings of dystonia and parkinsonism through the clinical lens of the conditions in which these movement disorders can be seen together. Foregrounding the discussion, we briefly review the circuits of the motor system and the neuroanatomical and neurophysiological aspects of motor control and highlight their relevance to the proposed pathophysiology of parkinsonism and dystonia. Insight into shared biology is then sought from dystonia occurring in PD and other forms of parkinsonism including those disorders in which both can be co-expressed simultaneously. We organize these within a biological schema along with important questions to be addressed in this space.
Early-onset inherited dystonias versus late-onset idiopathic dystonias: Same or different biological mechanisms?
Erro R, Monfrini E, Di Fonzo A
Int Rev Neurobiol · 2023 · PMID 37482397 · Publisher ↗
Dystonia syndromes encompass a heterogeneous group of movement disorders which might be differentiated by several clinical-historical features. Among the latter, age-at-onset is probably the most important in predicting...
Dystonia syndromes encompass a heterogeneous group of movement disorders which might be differentiated by several clinical-historical features. Among the latter, age-at-onset is probably the most important in predicting the likelihood both for the symptoms to spread from focal to generalized and for a genetic cause to be found. Accordingly, dystonia syndromes are generally stratified into early-onset and late-onset forms, the former having a greater likelihood of being monogenic disorders and the latter to be possibly multifactorial diseases, despite being currently labeled as idiopathic. Nonetheless, there are several similarities between these two groups of dystonia, including shared pathophysiological and biological mechanisms. Moreover, there is also initial evidence of age-related modifiers of early-onset dystonia syndromes and of critical periods of vulnerability of the sensorimotor network, during which a combination of genetic and non-genetic insults is more likely to produce symptoms. Based on these lines of evidence, we reappraise the double-hit hypothesis of dystonia, which would accommodate both similarities and differences between early-onset and late-onset dystonia in a single framework.
Adult-onset focal dystonias: To lump or split.
Jinnah HA, DeFazio G
Int Rev Neurobiol · 2023 · PMID 37482396 · Publisher ↗
The adult-onset focal dystonias are a group of clinically heterogeneous disorders that affect different regions of the body. Although they affect different regions with different clinical manifestations, there is evidenc...
The adult-onset focal dystonias are a group of clinically heterogeneous disorders that affect different regions of the body. Although they affect different regions with different clinical manifestations, there is evidence that etiopathogenesis is shared at the anatomical, physiological, and genetic levels. However, there is also evidence that etiopathogenesis varies. This chapter summarizes the evidence for lumping or splitting these apparently different clinical phenotypes. It also includes some potential explanations to explain the similarities and differences.
Experimental pharmacology: Targeting metabolic pathways.
Leuzzi V, Galosi S
Int Rev Neurobiol · 2023 · PMID 37482395 · Publisher ↗
Since the discovery of the treatment for Wilson disease a growing number of treatable inherited dystonias have been identified and their search and treatment have progressively been implemented in the clinics of patients...
Since the discovery of the treatment for Wilson disease a growing number of treatable inherited dystonias have been identified and their search and treatment have progressively been implemented in the clinics of patients with dystonia. While waiting for gene therapy to be more widely and adequately translated into the clinical setting, the efforts to divert the natural course of dystonia reside in unveiling its pathogenesis. Specific metabolic treatments can rewrite the natural history of the disease by preventing neurotoxic metabolite accumulation or interfering with the cell accumulation of damaging metabolites, restoring energetic cell fuel, supplementing defective metabolites, and supplementing the defective enzyme. A metabolic derangement of cell homeostasis is part of the progression of many non-metabolic genetic lesions and could be the target for possible metabolic approaches. In this chapter, we provided an update on treatment strategies for treatable inherited dystonias and an overview of genetic dystonias with new experimental therapeutic approaches available or close to clinical translation.
Advances in targeting neurotransmitter systems in dystonia.
Steel D, Reid KM, Pisani A … +3 more , Hess EJ, Fox S, Kurian MA
Int Rev Neurobiol · 2023 · PMID 37482394 · Publisher ↗
Dystonia is characterised as uncontrolled, often painful involuntary muscle contractions that cause abnormal postures and repetitive or twisting movements. These movements can be continuous or sporadic and affect differe...
Dystonia is characterised as uncontrolled, often painful involuntary muscle contractions that cause abnormal postures and repetitive or twisting movements. These movements can be continuous or sporadic and affect different parts of the body and range in severity. Dystonia and its related conditions present a huge cause of neurological morbidity worldwide. Although therapies are available, achieving optimal symptom control without major unwanted effects remains a challenge. Most pharmacological treatments for dystonia aim to modulate the effects of one or more neurotransmitters in the central nervous system, but doing so effectively and with precision is far from straightforward. In this chapter we discuss the physiology of key neurotransmitters, including dopamine, noradrenaline, serotonin (5-hydroxytryptamine), acetylcholine, GABA, glutamate, adenosine and cannabinoids, and their role in dystonia. We explore the ways in which existing pharmaceuticals as well as novel agents, currently in clinical trial or preclinical development, target dystonia, and their respective advantages and disadvantages. Finally, we discuss current and emerging genetic therapies which may be used to treat genetic forms of dystonia.
What can epidemiological studies teach on the pathophysiology of adult-onset isolated dystonia?
Martino D
Int Rev Neurobiol · 2023 · PMID 37482393 · Publisher ↗
Several demographic and environmental factors may play an important role in determining the risk of developing adult-onset isolated dystonia (AOID) and/or modifying its course. However, epidemiologic studies have provide...
Several demographic and environmental factors may play an important role in determining the risk of developing adult-onset isolated dystonia (AOID) and/or modifying its course. However, epidemiologic studies have provided to date only partial insight on the disease mechanisms that are actively influenced by these factors. The age-related increase in female predominance in both patients diagnosed with AOID and subjects carrying its putative mediational phenotype suggests sexual dimorphism that has been demonstrated for mechanisms related to blepharospasm and cervical dystonia. The opposite relationship that spread and spontaneous remission of AOID have with age suggests age-related decline of compensatory mechanisms that protect from the progression of AOID. Epidemiological studies focusing on environmental risk factors yielded associations only with specific forms of AOID, even for those factors that are not likely to predispose exclusively to specific focal forms (for example, only writing dystonia was found associated with head trauma, and only blepharospasm with coffee intake). Other factors show biological plausibility of their mechanistic role for specific forms, e.g., dry eye syndrome or sunlight exposure for blepharospasm, scoliosis for cervical dystonia, repetitive writing for writing dystonia. Overall, the relationship between environment and AOID remains complex and incompletely defined. Both hypothesis-driven preclinical studies and well-designed cross-sectional or prospective clinical studies are still necessary to decipher this intricate relationship.
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