Current knowledge and challenges associated with targeted delivery of neurotrophic factors into the central nervous system: focus on available approaches

AbstractDuring the last decades, numerous basic and clinical studies have been conducted to assess the delivery efficiency of therapeutic agents into the brain and spinal cord parenchyma using several administration routes. Among conventional and in-progress administrative routes, the eligibility of stem cells, viral vectors, and biomaterial systems have been shown in the delivery of NTFs. Despite these manifold advances, the close association between the delivery system and regeneration outcome remains unclear. Herein, we aimed to discuss recent progress in the delivery of these factors and the pros and cons related to each modality.

Download Full-text

Plectin in the Central Nervous System and a Putative Role in Brain Astrocytes

Cells ◽

10.3390/cells10092353 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2353

Author(s):

Maja Potokar ◽

Jernej Jorgačevski

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Current Knowledge ◽

Cell Types ◽

Cellular Proteins ◽

Bidirectional Communication ◽

The Central Nervous System ◽

Brain And Spinal Cord ◽

The Brain

Plectin, a high-molecular-mass cytolinker, is abundantly expressed in the central nervous system (CNS). Currently, a limited amount of data about plectin in the CNS prevents us from seeing the complete picture of how plectin affects the functioning of the CNS as a whole. Yet, by analogy to its role in other tissues, it is anticipated that, in the CNS, plectin also functions as the key cytoskeleton interlinking molecule. Thus, it is likely involved in signalling processes, thereby affecting numerous fundamental functions in the brain and spinal cord. Versatile direct and indirect interactions of plectin with cytoskeletal filaments and enzymes in the cells of the CNS in normal physiological and in pathologic conditions remain to be fully addressed. Several pathologies of the CNS related to plectin have been discovered in patients with plectinopathies. However, in view of plectin as an integrator of a cohesive mesh of cellular proteins, it is important that the role of plectin is also considered in other CNS pathologies. This review summarizes the current knowledge of plectin in the CNS, focusing on plectin isoforms that have been detected in the CNS, along with its expression profile and distribution alongside diverse cytoskeleton filaments in CNS cell types. Considering that the bidirectional communication between neurons and glial cells, especially astrocytes, is crucial for proper functioning of the CNS, we place particular emphasis on the known roles of plectin in neurons, and we propose possible roles of plectin in astrocytes.

Download Full-text

On the invasion of the central nervous system by nematodes I. The Incidence and pathological significance of nematodes in the central nervous system

Parasitology ◽

10.1017/s0031182000027402 ◽

1955 ◽

Vol 45 (1-2) ◽

pp. 31-40 ◽

Cited By ~ 35

Author(s):

J. F. A. Sprent

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Close Association ◽

Nematode Species ◽

Cellular Infiltration ◽

Pathological Changes ◽

The Central Nervous System ◽

Brain And Spinal Cord ◽

The Brain

A wide variety of nematode species have been observed to invade the central nervous system. They may be located in the meningeal spaces or may penetrate into the tissues of the brain and spinal cord.The pathological changes resulting from invasion of the central nervous system are influenced by the route of entry, the size and the mobility of the parasite. They may be diffuse or focal and may include haemorrhage, degenerative changes, cellular infiltration and glial proliferation. Such changes may or may not be observed in close association with the parasite.Symptoms indicating involvement of the central nervous system have long been associated with nematode infections outside the central nervous system. The pathogenesis of these symptoms is obscure, but they may possibly be of allergic origin.The direct pathological effects on the central nervous system are mainly the result of trauma and are directly proportional to the size and activity of the parasite. The possibility that nematodes may transport viruses into the central nervous system is briefly discussed.

Download Full-text

Novel Enzyme Replacement Therapies for Neuropathic Mucopolysaccharidoses

International Journal of Molecular Sciences ◽

10.3390/ijms21020400 ◽

2020 ◽

Vol 21 (2) ◽

pp. 400 ◽

Cited By ~ 4

Author(s):

Yuji Sato ◽

Torayuki Okuyama

Keyword(s):

Current Knowledge ◽

Enzyme Replacement ◽

Administration Routes ◽

Neuropsychiatric Manifestations ◽

Hereditary Disorders ◽

The Central Nervous System ◽

The Common ◽

Available Information ◽

The Brain ◽

Cns Lesions

Although the advent of enzyme replacement therapy (ERT) for mucopolysaccharidoses (MPS) has paved the way for the treatment for these hereditary disorders, the blood brain barrier (BBB) has prevented patients with MPS involving the central nervous system (CNS) from benefitting from ERT. Therefore, finding ways to increase drug delivery into the brain across the BBB remains a crucial challenge for researchers and clinicians in the field. Attempts have been made to boost brain uptake of enzymes by targeting various receptors (e.g., insulin and transferrin), and several other administration routes have also been tested. This review summarizes the available information on clinical trials (completed, ongoing, and planned) of novel therapeutic agents with efficacy against CNS symptoms in neuropathic MPS and also discusses the common associated challenges and pitfalls, some of which may help elucidate the pathogenesis of the neurodegeneration leading to the manifold CNS symptoms. A summary of current knowledge pertaining to the neuropathological progression and resultant neuropsychiatric manifestations is also provided, because it should be useful to ERT researchers looking for better approaches to treating CNS lesions in MPS.

Download Full-text

Comparisons of neuroinflammation, microglial activation, and degeneration of the locus coeruleus-norepinephrine system in APP/PS1 and aging mice

Journal of Neuroinflammation ◽

10.1186/s12974-020-02054-2 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Song Cao ◽

Daniel W. Fisher ◽

Guadalupe Rodriguez ◽

Tian Yu ◽

Hongxin Dong

Keyword(s):

Spinal Cord ◽

Locus Coeruleus ◽

Microglial Activation ◽

Healthy Aging ◽

Cell Types ◽

Norepinephrine System ◽

Protective Processes ◽

The Central Nervous System ◽

Brain And Spinal Cord ◽

The Brain

Abstract Background The role of microglia in Alzheimer’s disease (AD) pathogenesis is becoming increasingly important, as activation of these cell types likely contributes to both pathological and protective processes associated with all phases of the disease. During early AD pathogenesis, one of the first areas of degeneration is the locus coeruleus (LC), which provides broad innervation of the central nervous system and facilitates norepinephrine (NE) transmission. Though the LC-NE is likely to influence microglial dynamics, it is unclear how these systems change with AD compared to otherwise healthy aging. Methods In this study, we evaluated the dynamic changes of neuroinflammation and neurodegeneration in the LC-NE system in the brain and spinal cord of APP/PS1 mice and aged WT mice using immunofluorescence and ELISA. Results Our results demonstrated increased expression of inflammatory cytokines and microglial activation observed in the cortex, hippocampus, and spinal cord of APP/PS1 compared to WT mice. LC-NE neuron and fiber loss as well as reduced norepinephrine transporter (NET) expression was more evident in APP/PS1 mice, although NE levels were similar between 12-month-old APP/PS1 and WT mice. Notably, the degree of microglial activation, LC-NE nerve fiber loss, and NET reduction in the brain and spinal cord were more severe in 12-month-old APP/PS1 compared to 12- and 24-month-old WT mice. Conclusion These results suggest that elevated neuroinflammation and microglial activation in the brain and spinal cord of APP/PS1 mice correlate with significant degeneration of the LC-NE system.

Download Full-text

Depression and Inflammatory Markers in Veterans With Multiple Sclerosis

Biological Research For Nursing ◽

10.1177/10998004211050082 ◽

2021 ◽

pp. 109980042110500

Author(s):

Pamela Newland ◽

Yelyzaveta Basan ◽

Ling Chen ◽

Gregory Wu

Keyword(s):

Multiple Sclerosis ◽

Inflammatory Markers ◽

Pearson Correlation ◽

Correlation Coefficients ◽

The United States ◽

Biological Mechanisms ◽

The Central Nervous System ◽

Brain And Spinal Cord ◽

The Brain

Multiple sclerosis (MS), an inflammatory neurodegenerative disease of the central nervous system (CNS), afflicts over one per thousand people in the United States. The pathology of MS typically involves lesions in several regions, including the brain and spinal cord. The manifestation of MS is variable and carries great potential to negatively impact quality of life (QOL). Evidence that inflammatory markers are related to depression in MS is accumulating. However, there are barriers in precisely identifying the biological mechanisms underlying depression and inflammation. Analysis of cytokines provides one promising approach for understanding the mechanisms that may contribute to MS symptoms. Methods: In this pilot study, we measured salivary levels of interleukin (IL)-6, IL-1beta (β), and IL-10 in 24 veterans with MS. Descriptive statistics were reported and Pearson correlation coefficients were obtained between cytokines and depression. Results: The anti-inflammatory cytokine IL-10 was significantly negatively associated with depression in veterans with MS (r = −0.47, p = .024). Conclusion: Cytokines may be useful for elucidating biological mechanisms associated with the depression and a measure for nurses caring for veterans with MS.

Download Full-text

A Case of Rhizomelic Chondrodysplasia Punctata in Newborn

Case Reports in Medicine ◽

10.1155/2014/879679 ◽

2014 ◽

Vol 2014 ◽

pp. 1-3 ◽

Cited By ~ 4

Author(s):

Nalan Karabayır ◽

Gonca Keskindemirci ◽

Erdal Adal ◽

Orhan Korkmaz

Keyword(s):

Soft Tissues ◽

Clinical Symptoms ◽

Current Knowledge ◽

Chondrodysplasia Punctata ◽

Long Bones ◽

Rhizomelic Chondrodysplasia Punctata ◽

Cervical Spinal Stenosis ◽

Brain And Spinal Cord ◽

The Brain ◽

Severe Growth

Rhizomelic chondrodysplasia punctate (RCDP) is a rare autosomal recessive peroxisomal disease. The main features of the disease are shortening of the proximal long bones, punctate calcifications located in the epiphyses of long bones and in soft tissues around joints and vertebral column, vertebral clefting, dysmorphic face, and severe growth retardation, whereas cervical spinal stenosis may also rarely be present. Imaging of the brain and spinal cord in patients with this disorder may aid prognosis and guide management decisions. We report the newborn diagnosed as CDP with cervical stenosis. Our aim is to discuss current knowledge on etiopathogenesis as well as radiological and clinical symptoms of diseases associated with CDP.

Download Full-text

Lipid Transport and Metabolism at the Blood-Brain Interface: Implications in Health and Disease

Frontiers in Physiology ◽

10.3389/fphys.2021.645646 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fabien Pifferi ◽

Benoit Laurent ◽

Mélanie Plourde

Keyword(s):

Fatty Acids ◽

Neurodegenerative Diseases ◽

Current Knowledge ◽

Lipid Transport ◽

Omega 3 ◽

Blood Brain ◽

Brain Interface ◽

The Central Nervous System ◽

Health And Disease ◽

The Brain

Many prospective studies have shown that a diet enriched in omega-3 polyunsaturated fatty acids (n-3 PUFAs) can improve cognitive function during normal aging and prevent the development of neurocognitive diseases. However, researchers have not elucidated how n-3 PUFAs are transferred from the blood to the brain or how they relate to cognitive scores. Transport into and out of the central nervous system depends on two main sets of barriers: the blood-brain barrier (BBB) between peripheral blood and brain tissue and the blood-cerebrospinal fluid (CSF) barrier (BCSFB) between the blood and the CSF. In this review, the current knowledge of how lipids cross these barriers to reach the CNS is presented and discussed. Implications of these processes in health and disease, particularly during aging and neurodegenerative diseases, are also addressed. An assessment provided here is that the current knowledge of how lipids cross these barriers in humans is limited, which hence potentially restrains our capacity to intervene in and prevent neurodegenerative diseases.

Download Full-text

Functional dichotomy in spinal- vs prefrontal-projecting locus coeruleus modules splits descending noradrenergic analgesia from ascending aversion and anxiety in rats

eLife ◽

10.7554/elife.29808 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 59

Author(s):

Stefan Hirschberg ◽

Yong Li ◽

Andrew Randall ◽

Eric J Kremer ◽

Anthony E Pickering

Keyword(s):

Locus Coeruleus ◽

Viral Vectors ◽

Spontaneous Pain ◽

Pain Model ◽

Axon Terminals ◽

Neuronal Populations ◽

Functional Organisation ◽

Neuropathic Pain Model ◽

Brain And Spinal Cord ◽

The Brain

The locus coeruleus (LC) projects throughout the brain and spinal cord and is the major source of central noradrenaline. It remains unclear whether the LC acts functionally as a single global effector or as discrete modules. Specifically, while spinal-projections from LC neurons can exert analgesic actions, it is not known whether they can act independently of ascending LC projections. Using viral vectors taken up at axon terminals, we expressed chemogenetic actuators selectively in LC neurons with spinal (LC:SC) or prefrontal cortex (LC:PFC) projections. Activation of the LC:SC module produced robust, lateralised anti-nociception while activation of LC:PFC produced aversion. In a neuropathic pain model, LC:SC activation reduced hind-limb sensitisation and induced conditioned place preference. By contrast, activation of LC:PFC exacerbated spontaneous pain, produced aversion and increased anxiety-like behaviour. This independent, contrasting modulation of pain-related behaviours mediated by distinct noradrenergic neuronal populations provides evidence for a modular functional organisation of the LC.

Download Full-text

ACCUMULATION OF ANTIBODIES IN THE CENTRAL NERVOUS SYSTEM

Journal of Experimental Medicine ◽

10.1084/jem.51.6.889 ◽

1930 ◽

Vol 51 (6) ◽

pp. 889-902 ◽

Cited By ~ 25

Author(s):

Jules Freund

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Cerebrospinal Fluid ◽

Slow Rate ◽

Immune Serum ◽

Brain Extract ◽

Rapid Rate ◽

The Central Nervous System ◽

Brain And Spinal Cord ◽

The Brain

1. Antibodies can be extracted from the brain and spinal cord of rabbits actively or passively immunized with typhoid bacilli. 2. The titers of the antibodies in the extracts of brain and cord depend upon the titer of the blood serum. In actively immunized rabbits the following numerical relationships exist between the titers of the serum and of these organ extracts: The ratio of the titer of the serum is to the titers of extract of brain and of the spinal cord about as 100 is to 0.8; the titer of the serum is to the titer of the cerebrospinal fluid as 100 is to 0.3. In passively immunized rabbits the titer of the serum is to the titer of brain and spinal-cord extract as 100 is to 0.7. 3. The antibodies recovered from the brain are not due to the presence of blood in it for perfusion of the brain does not reduce its antibody content appreciably. 4. Antibodies penetrate into the spinal fluid from the blood even in the absence of inflammation of the meninges. When the penetration is completed the following numerical relationship exists between the titer of the serum and that of the cerebrospinal fluid: 100 to 0.25. 5. The penetration into the cerebrospinal fluid of antibodies injected intravenously proceeds at a slow rate, being completed only several hours after the immune serum has been injected. The penetration of antibodies into the tissue of the brain occurs at a very rapid rate. It is completed within 15 minutes. 6. It is very unlikely that when the immune serum is injected intravenously the antibodies reach the brain tissue by way of the cerebrospinal fluid, for (1) the antibody titer of the cerebrospinal fluid is lower than that of the brain extract, and (2) antibodies penetrate faster into the tissue of the brain than into the cerebrospinal fluid.

Download Full-text

Multiple nocardial abscesses of the brainstem and spinal cord diagnosed after an open biopsy through a cervical partial central corpectomy: case report

Journal of Neurosurgery Spine ◽

10.3171/2014.12.spine14755 ◽

2015 ◽

Vol 23 (3) ◽

pp. 290-293 ◽

Cited By ~ 2

Author(s):

Ian Peeters ◽

Jan W. Casselman ◽

Stefaan J. Vandecasteele ◽

Alexander Janssen ◽

Bart Regaert ◽

...

Keyword(s):

Spinal Cord ◽

Cervical Spinal Cord ◽

Emission Tomography ◽

Open Biopsy ◽

Difficult Diagnosis ◽

Positron Emission ◽

The Central Nervous System ◽

Walking Difficulty ◽

Brain And Spinal Cord ◽

The Brain

Nocardiosis of the central nervous system is a challenging and difficult diagnosis for the clinician. The combination of infections of the brain and spinal cord is even more rare. The authors report on a patient with multiple lesions in the brainstem and cervical spinal cord. This 81-year-old immunocompetent woman presented with symptoms of progressive walking difficulty and ataxia. The results of an extensive workup with laboratory investigation, MRI, lumbar puncture, positron emission tomography (PET), and bone marrow biopsy remained inconclusive. Only after an open biopsy of a cervical lesion by an anterior approach through a partial central corpectomy of the cervical spine, was the diagnosis of nocardiosis made, allowing for specific antibiotic treatment.

Download Full-text