CNS Research
Membrane proteins are the most successful class of therapeutic targets. Creative Biolabs has developed a comprehensive collection of membrane protein in vitro assays for drug discovery that cover most membrane protein targets.
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Membrane protein stable cell lines are widely used in many areas of biomedical research. Creative Biolabs can offer membrane protein stable cell lines to stablish in vitro models for High Throughput Screening.
Creative Biolabs' membrane preparations are useful for membrane protein research. We offer membrane preparations to study the role of membrane proteins in diseases. Membrane preparations from Creative Biolabs are quality-assured frozen membranes from cells expressing recombinant or natural receptors.
Creative Biolabs offers high-quality, innovative tools to help research groups accelerate membrane protein drug discovery. They can be found by targets. If there is no product that meets your needs, please contact us.
The vertebrate central nervous system (CNS) has evolved from a relatively simple and morphologically consistent neural tube to a highly complex structure. The mechanisms that regulate early neural tube patterns have been intensively studied in the last decade. During early development, the neural tube is divided into longitudinal and transverse subdivisions. Each embryonic subdivision represents a histogenetic domain undergoing additional regionalization and morphogenesis, culminating in mature functional structures such as brain nuclei and layers. They are connected by bundles of fibers that form the mature brain's functional systems and neural circuits.
Fig.1 The six major divisions of the central nervous system. (Pamela, et al., 2011)
Schizophrenia
Schizophrenia has a lifetime prevalence of about 1% and accounts for a huge healthcare burden, with associated annual costs estimated to be more than $150 billion in the United States. The fact that a disorder affecting around 1% of the population is associated with such cost is attributable to the typical onset in early adulthood and the long-term impairments in social and occupational function associated with the disease. The disorder is also associated with reduced life expectancy: someone with schizophrenia has a mean life expectancy of about 15 years shorter than the general population and a 5% to 10% lifetime risk of death by suicide.
Addiction
Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, often drug usage, despite substantial harm and other negative consequences. In addition, repetitive drug use often alters brain function in ways that perpetuate craving.
In severe addiction, individuals spend much time and effort procuring drugs for subsequent use that may not be in rich supply or immediately available, despite the considerable risk of personal, physical, and social harm.
Fig.2 Model of interacting circuits in which disruptions contribute to compulsive-like behaviors underlying drug addiction. (George, et al., 2016)
Parkinson's disease (PD)
PD is a recognizable clinical syndrome with various causes and clinical presentations. PD has a significant effect on society. In terms of the number of people affected, this disease is a common condition, with approximately 6.1 million people who had been affected worldwide in 2016. For reasons that are not yet fully understood, the incidence and prevalence of this disease have risen rapidly in the past two decades.
Fig.3 Sites of action for the various anti-PD drugs. (Bastiaan, et al., 2021)
Alzheimer's disease (AD)
AD is one of the most common neurodegenerative diseases and accounts for more than 80% of dementia cases worldwide in older people. It leads to the progressive loss of mental, behavioral, and functional decline and learning ability. Approximately 200,000 people younger than 65 years with AD comprise the younger onset AD population; 5 million are aged 65 years or older. By 2050, one new case of AD is expected to develop every 33 seconds or nearly a million new cases per year, and the estimated prevalence is expected to be 13.8 million.
Fig.4 AD and its pathogenesis. (Maryam, et al., 2021)
Membrane Protein in CNS Research
A functional pool of proteins is ensured by continuous synthesis and degradation of the homeostatic regulation of protein synthesis and interpretation. The complexity of neuronal lifespan and morphology represents a challenge for cytosolic and membrane protein turnover. Proteasomal degradation primarily affects cytoplasmic proteins, whereas membrane proteins are cleaved through the lysosomal pathway or autophagy. Problems in the function of cytoplasmic and membrane protein degradation can lead to protein accumulation, ultimately leading to neuronal dysfunction. This defect is a hallmark of many neurodegenerative diseases.
Fig.5 Three models for where neuronal membrane proteins sort and degrade. (Eugene, et al., 2018)
- Blood-Brain Barrier (BBB)
The BBB is a fundamental part of the CNS. Its functional and structural integrity is critical for maintaining the homeostasis of the brain microenvironment by controlling the passage of substances and regulating the transport of immune cells between the blood and the brain.
| Pathophysiology of BBB Disruption | Associated Diseases | Therapeutic Targets |
|---|---|---|
| Upregulation of VEGF and Activation of VEGFR2 | ALS, AD, PD, epilepsy, ischemic stroke | Anti-VEGF antibody and VEGFR 2 inhibitor |
| eNOS activation | Stroke and TBI | Selective eNOS inhibitor |
| Upregulation of MMPs | Schizophrenia, Stroke, and TBI | Inhibition of MMPs |
| Activation of endothelin receptors, ETA, ETB | Stroke and epilepsy | Inhibition of ETA and ETB |
| Downregulation of VE-Cadherine | MS, Stroke | Inhibition of miR-27a/VE by CD5-2; antibody against ICAM |
| Disorganization of adherens junctions | MS, Stroke | Stabilize the adherens junctions |
| Reduced expression of TJ proteins | Depression, Stroke, Stress, | Induction of TJs protein expression |
| Imbalance of AMP-activated protein kinase pathway | Stroke | Activation of AMP-activated protein kinase pathway |
| Activation or upregulation of inflammatory cytokines e.g., TNF-β, IL-1β, TNF-α and IL-6 |
Stroke, TBI, Cognitive impairments, Seizures, MS |
Inhibition of inflammatory cytokines |
| Oxidative stress induction by activation of NOX4 and NOX5 | Stroke | Selective inhibition of NOX4 or NOX5 |
| Contraction of actin-myosin cytoskeleton via myosin light chain Phosphorylation | Stroke | Inhibition of RhoA/Rho-associated proteins kinase (ROCK) |
| Upregulation of MMPs | Stroke, TBI and Schizophrenia | Inhibition of MMP2/9 |
References
- Pamela, G.; et al. Inference of a human brain fiber bundle atlas from high angular resolution diffusion imaging. 2011.
- George, F.; et al. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016, 3, 760-73
- Bastiaan, R.; et al. Parkinson's disease. Lancet. 2021, 397, 2284-303.
- Maryam, F.; et al. Nanomaterials in Alzheimer's disease treatment: a comprehensive review. Nanomaterials for Biomedical Applications. 2021, 26(10), 851-865.
- Eugene, J.; et al. The where, what, and when of membrane protein degradation in neurons. Developmental Neurobiology. 2018, 78(3), 283-29.
