Estrogen α and ß Receptor Expression in the Various Regions of Resected Glioblastoma Multiforme Tumors and in an In Vitro Model.

Glioblastoma multiforme (GBM) is a malignant tumor with a higher prevalence in men and a higher survival rate in transmenopausal women. It exhibits distinct areas influenced by changing environmental conditions. This study examines how these areas differ in the levels of estrogen receptors (ERs) which play an important role in the development and progression of many cancers, and whose expression levels are often correlated with patient survival. This study utilized two research models: an in vitro model employing the U87 cell line and a second model involving tumors resected from patients (including tumor core, enhancing tumor region, and peritumoral area). ER expression was assessed at both gene and protein levels, with the results validated using confocal microscopy and immunohistochemistry. Under hypoxic conditions, the U87 line displayed a decrease in ERß mRNA expression and an increase in ERα mRNA expression. In patient samples, ERß mRNA expression was lower in the tumor core compared to the enhancing tumor region (only in males when the study group was divided by sex). In addition, ERß protein expression was lower in the tumor core than in the peritumoral area (only in women when the study group was divided by sex). Immunohistochemical analysis indicated the highest ERß protein expression in the enhancing tumor area, followed by the peritumoral area, and the lowest in the tumor core. The findings suggest that ER expression may significantly influence the development of GBM, exhibiting variability under the influence of conditions present in different tumor areas.

The Effects of Neuromonitoring and Cerebrolysin Administration on Outcomes in Patients with Traumatic Brain Injury-An Interventional Pilot Study.

INTRODUCTION: Traumatic brain injury (TBI) is one of the most common causes of death and an important burden to the worldwide healthcare system and society. There is a lack of guidelines for types of monitoring or neuroprotective therapy. The aim of this pilot study was to assess its feasibility and, furthermore, to evaluate the impact of Cerebrolysin on the following clinical outcomes: length of stay, Glasgow Outcome Scale (GOS) and mortality. METHODS: A cohort of 56 patients was included in this non-randomised, real-time, pre-post-interventional study. The patients were assessed with the Glasgow Coma Scale (GCS) and divided into two groups: severe (GCS < 8) and non-severe (GCS > 8). After the radiological examination (CT scan), the patients were qualified for an immediate neurosurgical procedure if needed. The patients were admitted to the intensive care unit, where a standardised protocol for TBI treatment was implemented. Additional neuromonitoring was applied. RESULTS: There were 56 patients (19 females; 33.9%), of which 41 were considered severe cases; the patients were allocated to the Cerebrolysin (n = 25) or control groups (n = 31). In a generalised linear model (GLM) approach, the use of Cerebrolysin was associated with a decrease in the probability of death in non-severe patients (by 0.333 (standard error (SE) = 0.157, p = 0.034)) but not in severe patients (estimate (Est.) = -0.115, SE = 0.127, p = 0.364). Patients who received Cerebrolysin and who were neuromonitored had favourable outcomes and better survival rates. CONCLUSIONS: A multimodal treatment approach with monitoring and Cerebrolysin may have a beneficial effect on patients with less severe TBIs; however, the present study has multiple limitations, and further research is needed.

Benefits of the Erector Spinae Plane Block before Cryoanalgesia in Children Undergoing Surgery for Funnel Chest Deformity.

Thoracic surgery causes significant pain despite standard multimodal analgesia. Intraoperative cryoanalgesia may be a solution. The onset of the clinical effect of cryoanalgesia can take 12-36 h. The addition of a regional anaesthesia before the cryoanalgesia procedure can enable analgesic protection for the patient during this period. The main aim of the study was to evaluate the benefits of the erector spinae plane (ESP) block prior to Nuss surgery. The 'control' group consisted of 10 teenagers who underwent cryoablation together with intravenous multimodal analgesia according to the standard protocol. The 'intervention' group included 26 teenage patients who additionally received an erector spinae plane block before operation. Pain relief (p = 0.015), opioid use (p = 0.009), independent physical activity and rehabilitation (p = 0.020) were faster in the intervention group. No features of local anaesthetic drug toxicity or complications of the ESP block were observed. The bilateral ESP block together with intraoperative intercostal nerve cryoablation performed prior to Nuss correction of funnel chest were more effective in terms of pain control.

Cerebrolysin in Patients with Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis.

Subarachnoid Hemorrhage (SAH) is one of the acute neurological conditions that is associated with high mortality and recovery failure rates. In recent years, due to the development of endovascular and classical techniques, the mortality rate after SAH has decreased. Currently, more research is focused on understanding the molecular mechanisms underlying SAH. Methods of treatment are investigated in order to obtain the best treatment result, not only survival. One of the drugs used in stroke, including SAH, is Cerebrolysin. It is a mixture of neuropeptides that has similar properties to neurotrophic factors. Its positive impact on strokes has been analyzed; however, there are no meta-analyses concerning only the subpopulation of patients diagnosed with SAH in the current literature. Therefore, we conducted a meta-analysis of available clinical trials to evaluate the effect of Cerebrolysin on the treatment outcome. The data suggest a positive effect of Cerebrolysin on the mortality of SAH patients. However, further randomized clinical trials with larger groups of patients are needed to draw final conclusions.

Reduced Expression of Very-Long-Chain Acyl-CoA Synthetases SLC27A4 and SLC27A6 in the Glioblastoma Tumor Compared to the Peritumoral Area.

This study aimed to analyze solute carrier family 27 (SLC27) in glioblastoma tumors. The investigation of these proteins will provide insight into how and to what extent fatty acids are taken up from the blood in glioblastoma tumors, as well as the subsequent fate of the up-taken fatty acids. Tumor samples were collected from a total of 28 patients and analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). The study also sought to explore the relationship between SLC27 expression and patient characteristics (age, height, weight, body mass index (BMI), and smoking history), as well as the expression levels of enzymes responsible for fatty acid synthesis. The expression of SLC27A4 and SLC27A6 was lower in glioblastoma tumors compared to the peritumoral area. Men had a lower expression of SLC27A5. Notably, a positive correlation was observed between the expression of SLC27A4, SLC27A5, and SLC27A6 and smoking history in women, whereas men exhibited a negative correlation between these SLC27s and BMI. The expression of SLC27A1 and SLC27A3 was positively correlated with the expression of ELOVL6. In comparison to healthy brain tissue, glioblastoma tumors take up fewer fatty acids. The metabolism of fatty acids in glioblastoma is dependent on factors such as obesity and smoking.

Cerebrolysin in Patients with TBI: Systematic Review and Meta-Analysis.

TBI (traumatic brain injury) is one of the most common causes of deaths and failure to return to society according to the latest statistics. Cerebrolysin is a drug approved for use in patients diagnosed with TBI. It is a mixture of neuropeptides derived from purified porcine brain proteins and multiple experimental studies have proven its neuroprotective and neurorestorative properties both in vitro and in vivo. In our meta-analysis, we analyze the latest clinical study reports on the use of Cerebrolysin in patients with TBI. The authors searched the databases: Pub Med, Cinahl, Web Of Science, and Embase from database inception until 11th July 2022. Ten clinical studies were eligible and included in the final analysis, including both retrospective and prospective studies of 8749 patients. Treatment with Cerebrolysin was associated with a statistically significant change in GCS and GOS. Mortality of any cause and the length of stay was not affected by the treatment. Our findings support and confirm the beneficial effects of Cerebrolysin treatment on the clinical outcome of patients after TBI. Further multi-center studies to optimize dosing and time of administration should be conducted.

Androgen Receptor Expression in the Various Regions of Resected Glioblastoma Multiforme Tumors and in an In Vitro Model.

Glioblastoma multiforme (GBM) is a malignant glioma, difficult to detect and with the lowest survival rates among gliomas. Its greater incidence among men and its higher survival rate among premenopausal women suggest that it may be associated with the levels of androgens. As androgens stimulate the androgen receptor (AR), which acts as a transcription factor, the aim of this study was the investigate the role of AR in the progression of GBM. The study was conducted on tissues collected from three regions of GBM tumors (tumor core, enhancing tumor region, and peritumoral area). In addition, an in vitro experiment was conducted on U-87 cells under various culture conditions (necrotic, hypoxic, and nutrient-deficient), mimicking the conditions in a tumor. In both of the models, androgen receptor expression was determined at the gene and protein levels, and the results were confirmed by confocal microscopy and immunohistochemistry. AR mRNA expression was higher under nutrient-deficient conditions and lower under hypoxic conditions in vitro. However, there were no differences in AR protein expression. No differences in AR mRNA expression were observed between the tested tumor structures taken from patients. No differences in AR mRNA expression were observed between the men and women. However, AR protein expression in tumors resected from patients was higher in the enhancing tumor region and in the peritumoral area than in the tumor core. In women, higher AR expression was observed in the peritumoral area than in the tumor core. AR expression in GBM tumors did not differ significantly between men and women, which suggests that the higher incidence of GBM in men is not associated with AR expression. In the group consisting of men and women, AR expression varied between the regions of the tumor: AR expression was higher in the enhancing tumor region and in the peritumoral area than in the tumor core, showing a dependence on tumor conditions (hypoxia and insufficient nutrient supply).

Glioblastoma Multiforme Tumors in Women Have a Lower Expression of Fatty Acid Elongases ELOVL2, ELOVL5, ELOVL6, and ELOVL7 than in Men.

One line of research on the possible ways of inhibiting the growth of glioblastoma multiforme (GBM), a brain tumor with a very poor prognosis, is the analysis of its metabolism, such as fatty acid synthesis by desaturases and elongases. This study examines the expression of elongases ELOVL1, ELOVL2, ELOVL3, ELOVL4, ELOVL5, ELOVL6, and ELOVL7 in GBM tumor samples from 28 patients (16 men and 12 women), using a quantitative real-time polymerase chain reaction (qRT-PCR). To demonstrate the influence of the tumor microenvironment on the tested elongases, U-87 MG cells were cultured in nutrient-deficient conditions and with cobalt chloride (CoCl2) as a hypoxia-mimetic agent. The results showed that the expression of ELOVL1 and ELOVL7 in the GBM tumor was lower than in the peritumoral area. The expression of six of the seven studied elongases differed between the sexes. Hypoxia increased the expression of ELOVL5 and ELOVL6 and decreased the expression of ELOVL1, ELOVL3, ELOVL4, and ELOVL7 in U-87 MG cells. These results indicate that the synthesis of fatty acids, especially polyunsaturated fatty acids (PUFA), in GBM tumors may be higher in men than in women. In contrast, the synthesis of saturated fatty acids (SFA) may be higher in women than in men.

CCL18 Expression Is Higher in a Glioblastoma Multiforme Tumor than in the Peritumoral Area and Causes the Migration of Tumor Cells Sensitized by Hypoxia.

Glioblastoma multiforme (GBM) is a brain tumor with a very poor prognosis. For this reason, researchers worldwide study the impact of the tumor microenvironment in GBM, such as the effect of chemokines. In the present study, we focus on the role of the chemokine CCL18 and its receptors in the GBM tumor. We measured the expression of CCL18, CCR8 and PITPNM3 in the GMB tumor from patients (16 men and 12 women) using quantitative real-time polymerase chain reaction. To investigate the effect of CCL18 on the proliferation and migration of GBM cells, experiments were performed using U-87 MG cells. The results showed that CCL18 expression was higher in the GBM tumor than in the peritumoral area. The women had a decreased expression of PITPNM3 receptor in the GBM tumor, while in the men a lower expression of CCR8 was observed. The hypoxia-mimetic agent, cobalt chloride (CoCl2), increased the expression of CCL18 and PITPNM3 and thereby sensitized U-87 MG cells to CCL18, which did not affect the proliferation of U-87 MG cells but increased the migration of the test cells. The results indicate that GBM cells migrate from hypoxic areas, which may be important in understanding the mechanisms of tumorigenesis.

Epidemiology of Glioblastoma Multiforme-Literature Review.

Glioblastoma multiforme (GBM) is one of the most aggressive malignancies, with a median overall survival of approximately 15 months. In this review, we analyze the pathogenesis of GBM, as well as epidemiological data, by age, gender, and tumor location. The data indicate that GBM is the higher-grade primary brain tumor and is significantly more common in men. The risk of being diagnosed with glioma increases with age, and median survival remains low, despite medical advances. In addition, it is difficult to determine clearly how GBM is influenced by stimulants, certain medications (e.g., NSAIDs), cell phone use, and exposure to heavy metals.

The Use of Ginkgo Biloba L. as a Neuroprotective Agent in the Alzheimer's Disease.

Alzheimer's disease, a neurodegenerative disease, is one of the most common causes of dementia if elderly people worldwide. Alzheimer's disease leads to the alienation of individuals and their exclusion from social and professional life. It is characterized mainly by the degradation of memory and disorientation, which occurs as a result of the loss of neuronal structure and function in different brain areas. In recent years, more and more attention has been paid to use in the treatment of natural bioactive compounds that will be effective in neurodegenerative diseases, including Alzheimer's disease. G. biloba L. and its most frequently used standardized extract (EGb 761), have been used for many years in supportive therapy and in the prevention of cognitive disorders. The paper presents an overview of reports on the pathogenesis of Alzheimer's disease, as well as a summary of the properties of G. biloba extract and its effects on the possible pathogenesis of the disease. By exploring more about the pathogenesis of the disease and the benefits of G. biloba extract for patients with Alzheimer's disease, it will be possible to create an individualized therapeutic protocol to optimize the treatment.

Atypical Pupil Reactions in Brain Dead Patients.

BACKGROUND: During routine diagnosis of brain death, changes in pupil diameter in response to the stimulation of peripheral nerves are sometimes observed. For example, pupillary dilation after diagnosed brain death is described in the literature as the ciliospinal reflex. However, pupil constriction creates diagnostic doubts. OBJECTIVE: The pupillometric analysis of pupil response to stimulation of the cervicothoracic spinal cord in patients with diagnosed brain death. METHODS: Instrumental tests to confirm the arrest of cerebral circulation were performed in 30 adult subjects (mean age 53.5 years, range 26-75 years) with diagnosed brain death. In addition, a pupillometer was used to measure the change in pupil diameter in response to neck flexion. INTERVENTION: Flexion of the neck and measuring the response in change of the pupil with the use of the pupillometer. RESULTS: The change in the pupil was observed in the examined group of patients. Difference in pupil size ≥ 0.2 mm was observed in 14 cases (46%). In five cases (17%), pupil constriction was found (from 0.2 to 0.7 mm). Measurement error was +/- 0.1 mm. CONCLUSIONS: Both pupillary constriction and dilatation may occur due to a ciliospinal reflex in patients with brain death. This phenomenon needs further research in order to establish its pathophysiology.

Epidemiology of Anthropometric Factors in Glioblastoma Multiforme-Literature Review.

Although glioblastoma multiforme (GBM) is a widely researched cancer of the central nervous system, we still do not know its full pathophysiological mechanism and we still lack effective treatment methods as the current combination of surgery, radiotherapy, and chemotherapy does not bring about satisfactory results. The median survival time for GBM patients is only about 15 months. In this paper, we present the epidemiology of central nervous system (CNS) tumors and review the epidemiological data on GBM regarding gender, age, weight, height, and tumor location. The data indicate the possible influence of some anthropometric factors on the occurrence of GBM, especially in those who are male, elderly, overweight, and/or are taller. However, this review of single and small-size epidemiological studies should not be treated as definitive due to differences in the survey methods used. Detailed epidemiological registers could help identify the main at-risk groups which could then be used as homogenous study groups in research worldwide. Such research, with less distortion from various factors, could help identify the pathomechanisms that lead to the development of GBM.

The Effect of Hypoxia on the Expression of CXC Chemokines and CXC Chemokine Receptors-A Review of Literature.

Hypoxia is an integral component of the tumor microenvironment. Either as chronic or cycling hypoxia, it exerts a similar effect on cancer processes by activating hypoxia-inducible factor-1 (HIF-1) and nuclear factor (NF-κB), with cycling hypoxia showing a stronger proinflammatory influence. One of the systems affected by hypoxia is the CXC chemokine system. This paper reviews all available information on hypoxia-induced changes in the expression of all CXC chemokines (CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8 (IL-8), CXCL9, CXCL10, CXCL11, CXCL12 (SDF-1), CXCL13, CXCL14, CXCL15, CXCL16, CXCL17) as well as CXC chemokine receptors-CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7 and CXCR8. First, we present basic information on the effect of these chemoattractant cytokines on cancer processes. We then discuss the effect of hypoxia-induced changes on CXC chemokine expression on the angiogenesis, lymphangiogenesis and recruitment of various cells to the tumor niche, including myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), regulatory T cells (Tregs) and tumor-infiltrating lymphocytes (TILs). Finally, the review summarizes data on the use of drugs targeting the CXC chemokine system in cancer therapies.

CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of the Ligands of Receptors CCR1, CCR2, CCR3, and CCR4.

CC chemokines, a subfamily of 27 chemotactic cytokines, are a component of intercellular communication, which is crucial for the functioning of the tumor microenvironment. Although many individual chemokines have been well researched, there has been no comprehensive review presenting the role of all known human CC chemokines in the hallmarks of cancer, and this paper aims at filling this gap. The first part of this review discusses the importance of CCL1, CCL3, CCL4, CCL5, CCL18, CCL19, CCL20, CCL21, CCL25, CCL27, and CCL28 in cancer. Here, we discuss the significance of CCL2 (MCP-1), CCL7, CCL8, CCL11, CCL13, CCL14, CCL15, CCL16, CCL17, CCL22, CCL23, CCL24, and CCL26. The presentation of each chemokine includes its physiological function and then the role in tumor, including proliferation, drug resistance, migration, invasion, and organ-specific metastasis of tumor cells, as well as the effects on angiogenesis and lymphangiogenesis. We also discuss the effects of each CC chemokine on the recruitment of cancer-associated cells to the tumor niche (eosinophils, myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), tumor-associated neutrophils (TAN), regulatory T cells (Treg)). On the other hand, we also present the anti-cancer properties of CC chemokines, consisting in the recruitment of tumor-infiltrating lymphocytes (TIL).

Hypoxia Alters the Expression of CC Chemokines and CC Chemokine Receptors in a Tumor-A Literature Review.

Hypoxia, i.e., oxygen deficiency condition, is one of the most important factors promoting the growth of tumors. Since its effect on the chemokine system is crucial in understanding the changes in the recruitment of cells to a tumor niche, in this review we have gathered all the available data about the impact of hypoxia on ß chemokines. In the introduction, we present the chronic (continuous, non-interrupted) and cycling (intermittent, transient) hypoxia together with the mechanisms of activation of hypoxia inducible factors (HIF-1 and HIF-2) and NF-κB. Then we describe the effect of hypoxia on the expression of chemokines with the CC motif: CCL1, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL24, CCL25, CCL26, CCL27, CCL28 together with CC chemokine receptors: CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10. To better understand the effect of hypoxia on neoplastic processes and changes in the expression of the described proteins, we summarize the available data in a table which shows the effect of individual chemokines on angiogenesis, lymphangiogenesis, and recruitment of eosinophils, myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), and tumor-associated macrophages (TAM) to a tumor niche.

Expression of SCD and FADS2 Is Lower in the Necrotic Core and Growing Tumor Area than in the Peritumoral Area of Glioblastoma Multiforme.

The expression of desaturases is higher in many types of cancer, and despite their recognized role in oncogenesis, there has been no research on the expression of desaturases in glioblastoma multiforme (GBM). Tumor tissue samples were collected during surgery from 28 patients (16 men and 12 women) diagnosed with GBM. The effect of necrotic conditions and nutritional deficiency (mimicking conditions in the studied tumor zones) was studied in an in vitro culture of human brain (glioblastoma astrocytoma) U-87 MG cells. Analysis of desaturase expression was made by qRT-PCR and the immunohistochemistry method. In the tumor, the expression of stearoyl-coenzyme A desaturase (SCD) and fatty acid desaturases 2 (FADS2) was lower than in the peritumoral area. The expression of other desaturases did not differ in between the distinguished zones. We found no differences in the expression of SCD, fatty acid desaturases 1 (FADS1), or FADS2 between the sexes. Necrotic conditions and nutritional deficiency increased the expression of the studied desaturase in human brain (glioblastoma astrocytoma) U-87 MG cells. The obtained results suggest that (i) biosynthesis of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) in a GBM tumor is less intense than in the peritumoral area; (ii) expressions of SCD, SCD5, FADS1, and FADS2 correlate with each other in the necrotic core, growing tumor area, and peritumoral area; (iii) expressions of desaturases in a GBM tumor do not differ between the sexes; and (iv) nutritional deficiency increases the biosynthesis of MUFA and PUFA in GBM cells.

Fractalkine/CX3CL1 in Neoplastic Processes.

Fractalkine/CX3C chemokine ligand 1 (CX3CL1) is a chemokine involved in the anticancer function of lymphocytes-mainly NK cells, T cells and dendritic cells. Its increased levels in tumors improve the prognosis for cancer patients, although it is also associated with a poorer prognosis in some types of cancers, such as pancreatic ductal adenocarcinoma. This work focuses on the 'hallmarks of cancer' involving CX3CL1 and its receptor CX3CR1. First, we describe signal transduction from CX3CR1 and the role of epidermal growth factor receptor (EGFR) in this process. Next, we present the role of CX3CL1 in the context of cancer, with the focus on angiogenesis, apoptosis resistance and migration and invasion of cancer cells. In particular, we discuss perineural invasion, spinal metastasis and bone metastasis of cancers such as breast cancer, pancreatic cancer and prostate cancer. We extensively discuss the importance of CX3CL1 in the interaction with different cells in the tumor niche: tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC) and microglia. We present the role of CX3CL1 in the development of active human cytomegalovirus (HCMV) infection in glioblastoma multiforme (GBM) brain tumors. Finally, we discuss the possible use of CX3CL1 in immunotherapy.

Morphine-element interactions - The influence of selected chemical elements on neural pathways associated with addiction.

Addiction is a pressing social problem worldwide and opioid dependence can be considered the strongest and most difficult addiction to treat. Mesolimbic and mesocortical dopaminergic pathways play an important role in modulation of cognitive processes and decision making and, therefore, changes in dopamine metabolism are considered the central basis for the development of dependence. Disturbances caused by excesses or deficiency of certain elements have a significant impact on the functioning of the central nervous system (CNS) both in physiological conditions and in pathology and can affect the cerebral reward system and therefore, may modulate processes associated with the development of addiction. In this paper we review the mechanisms of interactions between morphine and zinc, manganese, chromium, cadmium, lead, fluoride, their impact on neural pathways associated with addiction, and on antinociception and morphine tolerance and dependence.

Perineuronal Nets and Their Role in Synaptic Homeostasis.

Extracellular matrix (ECM) molecules that are released by neurons and glial cells form perineuronal nets (PNNs) and modulate many neuronal and glial functions. PNNs, whose structure is still not known in detail, surround cell bodies and dendrites, which leaves free space for synapses to come into contact. A reduction in the expression of many neuronal ECM components adversely affects processes that are associated with synaptic plasticity, learning, and memory. At the same time, increased ECM activity, e.g., as a result of astrogliosis following brain damage or in neuroinflammation, can also have harmful consequences. The therapeutic use of enzymes to attenuate elevated neuronal ECM expression after injury or in Alzheimer's disease has proven to be beneficial by promoting axon growth and increasing synaptic plasticity. Yet, severe impairment of ECM function can also lead to neurodegeneration. Thus, it appears that to ensure healthy neuronal function a delicate balance of ECM components must be maintained. In this paper we review the structure of PNNs and their components, such as hyaluronan, proteoglycans, core proteins, chondroitin sulphate proteoglycans, tenascins, and Hapln proteins. We also characterize the role of ECM in the functioning of the blood-brain barrier, neuronal communication, as well as the participation of PNNs in synaptic plasticity and some clinical aspects of perineuronal net impairment. Furthermore, we discuss the participation of PNNs in brain signaling. Understanding the molecular foundations of the ways that PNNs participate in brain signaling and synaptic plasticity, as well as how they change in physiological and pathological conditions, may help in the development of new therapies for many degenerative and inflammatory diseases of the brain.