International review of neurobiology最新文献

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_2A 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_2A 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_2A antagonism on dystonia was discussed in view of clinical studies of PD with postural abnormalities and the findings of dystonia mouse models.

Dopaminergic therapy for Parkinson's disease has revolutionised the treatment of the motor symptoms of the illness. However, it does not alleviate all components of the motor deficits and has only limited effects on non-motor symptoms. For this reason, alternative non-dopaminergic approaches to treatment have been sought and the adenosine A_2A receptor provided a novel target for symptomatic therapy both within the basal ganglia and elsewhere in the brain. Despite an impressive preclinical profile that would indicate a clear role for adenosine A_2A antagonists in the treatment of Parkinson's disease, the road to clinical use has been long and full of difficulties. Some aspects of the drugs preclinical profile have not translated into clinical effectiveness and not all the clinical studies undertaken have had a positive outcome. The reasons for this will be explored and suggestions made for the further development of this drug class in the treatment of Parkinson's disease. However, one adenosine A_2A antagonist, namely istradefylline has been introduced successfully for the treatment of late-stage Parkinson's disease in two major areas of the world and has become a commercial success through offering the first non-dopaminergic approach to the treatment of unmet need to be introduced in several decades.

Delivering drugs to the brain has always been a challenging task due to the restrictive properties of the blood-brain barrier (BBB). Intranasal delivery is therefore emerging as an efficient method of administration, making it easy to self-administration and thus provides a non-invasive and painless alternative to oral and parenteral administration for delivering therapeutics to the central nervous system (CNS). Recently, drug formulations have been developed to further enhance this nose-to-brain transport, primarily using nanoparticles (NPs). Therefore, the purposes of this review are to highlight and describe the anatomical basis of nasal-brain pathway and provide an overview of drug formulations and current drugs for intranasal administration in CNS disease.

The adenosine A_2A receptor (A_2AR) is abundantly expressed in the brain, including both neurons and glial cells. While the expression of A_2AR is relative low in glia, its levels elevate robustly in astrocytes and microglia under pathological conditions. Elevated A_2AR 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.

Concussive head injury (CHI) is one of the major risk factors for developing Parkinson's disease in later life of military personnel affecting lifetime functional and cognitive disturbances. Till date no suitable therapies are available to attenuate CHI or PD induced brain pathology. Thus, further exploration of novel therapeutic agents are highly warranted using nanomedicine in enhancing the quality of life of veterans or service members of US military. Since PD or CHI induces oxidative stress and perturbs neurotrophic factors regulation associated with phosphorylated tau (p-tau) deposition, a possibility exists that nanodelivery of agents that could enhance neurotrophic factors balance and attenuate oxidative stress could be neuroprotective in nature. In this review, nanowired delivery of cerebrolysin-a balanced composition of several neurotrophic factors and active peptide fragments together with monoclonal antibodies to neuronal nitric oxide synthase (nNOS) with p-tau antibodies was examined in PD following CHI in model experiments. Our results suggest that combined administration of nanowired antibodies to nNOS and p-tau together with cerebrolysin significantly attenuated CHI induced exacerbation of PD brain pathology. This combined treatment also has beneficial effects in CHI or PD alone, not reported earlier.

Astrocytes are highly involved in a multitude of developmental processes that are known to be dysregulated in Fragile X Syndrome. Here, we examine these processes individually and review the roles astrocytes play in contributing to the pathology of this syndrome. As a growing area of interest in the field, new and exciting insight is continually emerging. Understanding these glial-mediated roles is imperative for elucidating the underlying molecular mechanisms at play, not only in Fragile X Syndrome, but also other ASD-related disorders. Understanding these roles will be central to the future development of effective, clinically-relevant treatments of these disorders.

Nicotine abuse is frequent worldwide leading to about 8 millions people die every year due to tobacco related diseases. Military personnel often use nicotine smoking that is about 12.8% higher than civilian populations. Nicotine smoking triggers oxidative stress and are linked to several neurodegenerative diseases such as Alzheimer's disease. Nicotine neurotoxicity induces significant depression and oxidative stress in the brain leading to neurovascular damages and brain pathology. Thus, details of nicotine neurotoxicity and factors influencing them require additional investigations. In this review, effects of engineered nanoparticles from metals Ag and Cu (50-60 nm) on nicotine neurotoxicity are discussed with regard to nicotine smoking. Military personnel often work in the environment where chances of nanoparticles exposure are quite common. In our earlier studies, we have shown that nanoparticles alone induces breakdown of the blood-brain barrier (BBB) and exacerbates brain pathology in animal models. In present investigation, nicotine exposure in with Ag or Cu nanoparticles intoxicated group exacerbated BBB breakdown, induce oxidative stress and aggravate brain pathology. Treatment with nanowired H-290/51 a potent chain-breaking antioxidant together with nanowired ondansetron, a potent 5-HT3 receptor antagonist significantly reduced oxidative stress, BBB breakdown and brain pathology in nicotine exposure associated with Ag or Cu nanoparticles intoxication. The functional significance of this findings and possible mechanisms of nicotine neurotoxicity are discussed based on current literature.

A biotechnology for personalized ex vivo gene therapy based on molecular genomic balancing of hematopoietic stem cell (HSC) chromatin with nucleosome monomers of human genomic DNA (hDNA^nmr) has been developed and implemented in the clinic to change (to "correct") mutant chromosome loci genomes of dominant HSC clones that form mono- and oligoclonal hematopoiesis during aging and major (oncological, cardiovascular, neurodegenerative and autoimmune) fatal immune-mediated diseases of civilization. A fundamentally new biotechnological approach has been applied to the delivery of genetic material into eukaryotic stem and progenitor cells by establishing an artificial "recombinogenic situation" in them to induce homologous recombination (equivalent replacement) of mutant DNA regions with healthy hDNA^nmr. In experimental preclinical trials, the effectiveness of genomic balancing technology has been proven to reduce the risk of sudden death in old animals and to increase the lifespan of outbred mice by 30% and Wistar rats by 57%. The improvement in their quality of life, compared with the control, is explained by an increase in the telomeric regions of the HSCs and HPCs chromosomes by 1.5-2 times. The potential of the technology to slow down the hereditary neurodegenerative diseases on the model of amyotrophic lateral sclerosis is shown. The effectiveness of this technology in clinical practice is presented on the example of a terminal patient with stage 4 neuroendocrine cancer. This technology used in the treatment of a number of oncological, neurodegenerative, autoimmune and hereditary diseases with clonal hematopoiesis is able to arrest the progression of the disease, prevent its recurrence, prolong the active life of a person, increase the average life expectancy and prevent sudden death.

Matrix metalloproteinase-9 (MMP-9) belongs to the family of endopeptidases expressed in neurons and secreted at the synapse in response to neuronal activity. It regulates the pericellular environment by cleaving its protein components. MMP9 is involved in activity-dependent reorganization of spine architecture. In the mouse model of fragile X syndrome (FXS), the most common inherited intellectual disability and the most common single-gene cause of autism, increased synaptic expression of MMP-9 is responsible for the observed dendritic spine abnormalities. In this chapter, I summarize the current data on the molecular regulatory pathways responsible for synaptic MMP-9 expression and discuss the fact that MMP-9 is extracellularly localized, making it a particularly attractive potential target for therapeutic pharmacological intervention in FXS.