Modulation Of Glial Cells Research Articles

A comparison of spinal Iba1 and GFAP expression in rodent models of acute and chronic pain

The treatment of acute and chronic pain is still deficient. The modulation of glial cells may provide novel targets to treat pain. We hypothesize that astrocytes and microglia participate in the initiation and maintenance of both, acute surgical and chronic neuropathic pain. Rats underwent paw incision, L5 nerve exposure or L5 nerve transection surgery. Behavioral mechanical allodynia was assessed using von Frey filaments. Immunohistochemistry was performed using anti-ionized calcium binding adaptor protein, Iba-1 (microglia), and anti-Glial Fibrillary Acidic Protein, GFAP (astrocytes) on day 1, 4 and 7 after surgery. Following paw incision and at spinal L5 segment GFAP expression was increased in laminae I–II and Iba1 in deep laminae on day 1, in the entire dorsal horn on day 4 and dissipated on day 7 after paw incision in parallel with the allodynia. L5 nerve transection induced mechanical allodynia from day 1 to 7 which correlated with Iba-1 increases on day 1, 4 (entire dorsal horn) and day 7 after nerve injury (deep laminae of the dorsal horn) at spinal L5 segment. Conversely, GFAP increased at later time points from day 4 (deep laminae) and on day 7 (entire dorsal horn). Our data demonstrates that astrocytes (GFAP expression) play a role in the initiation of acute pain and the maintenance of chronic pain while Iba-1 increases closely correlated with the early phase of neuropathic pain. Iba1 and GFAP increased rostrally, at L3 segment, after paw incision (day 4) and only Iba1 increased following L5 nerve transection (day 7).

Differential Regulation of the Renin-Angiotensin System by Nicotine in WKY and SHR Glia

Given that (1) the renin-angiotensin system (RAS) is compartmentalized within the central nervous system in neurons and glia (2) the major source of brain angiotensinogen is the glial cells, (3) the importance of RAS in the central control of blood pressure, and (4) nicotine increases the probability of development of hypertension associated to genetic predisposition; the objective of the present study was to evaluate the effects of nicotine on the RAS in cultured glial cells from the brainstem and hypothalamus of Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Ligand binding, real-time PCR and western blotting assays were used to compare the expression of angiotensinogen, angiotensin converting enzyme, angiotensin converting enzyme 2 and angiotensin II type1 receptors. We demonstrate, for the first time, that there are significant differences in the basal levels of RAS components between WKY and SHR rats in glia from 1-day-old rats. We also observed that nicotine is able to modulate the renin-angiotensin system in glial cells from the brainstem and hypothalamus and that the SHR responses were more pronounced than WKY ones. The present data suggest that nicotine effects on the RAS might collaborate to the development of neurogenic hypertension in SHR through modulation of glial cells.

Modulation and impact of class I major histocompatibility complex by neural stem cell-derived neurotrophins on neuroregeneration

Transplantation of neural stem cells (NSC) has shown to elicit functional recovery in experimental animal and human models of neural disorders pertaining to cell loss or degeneration. However, the underlying mechanisms of the regimen are not well understood. The scenarios lead to the speculation of neuroregeneration and replacement of lost neurons in both the central nervous system (CNS) and the peripheral nervous system (PNS). The repair per se is extremely complex involving the re-building and modulation of synapses, neurites, neural cells and glial cells. Neurotrophins, which nourish the CNS and the PNS, may attribute to the functional improvement after neural stem cell transplantation. Recent studies suggested the CNS plasticity may be modulated by the class I major histocompatibility complex (MHC), which are in turn regulated by neurotrophins. Based upon these findings, we speculate that the neurotrophins derived from the transplanted NSC may modulate the expression of the major histocompatibility complex in the injured microenvironment to facilitate neurological recovery. The proposition may have clues on the development of novel treatment modality to cure CNS injury.

Excitotoxicity induced neuronal cell loss is prevented by the HSV-2 vector ΔRR through activation of survival pathways and modulation of glial cells

Excitotoxicity induced neuronal cell loss is prevented by the HSV-2 vector ΔRR through activation of survival pathways and modulation of glial cells

1069. The HSV-2 Vector ΔRR Prevents Excitotoxicity-Induced Neuronal Cell Loss through Activation of Survival Pathways and Glial Cell Modulation

Gene therapy of neurodegenerative diseases is of significant current interest, but the identification of appropriate gene targets and effective delivery platforms has proven to be a major stumbling block. We constructed a novel, growth compromised HSV-2 based vector, ΔRR, which utilizes the viral anti-apoptotic gene ICP10PK to protect neurons from excitotoxic injury in animal models of temporal lobe epilepsy. In this model, intranasally delivered ΔRR evidenced no toxicity and the anti-apoptotic gene ICP10PK was expressed in tissues along the olfactory bulb route as determined by immunoblotting and/or immunohistochemistry.

Calcium waves propagate through radial glial cells and modulate proliferation in the developing neocortex.

The majority of neurons in the adult neocortex are produced embryonically during a brief but intense period of neuronal proliferation. The radial glial cell, a transient embryonic cell type known for its crucial role in neuronal migration, has recently been shown to function as a neuronal progenitor cell and appears to produce most cortical pyramidal neurons. Radial glial cell modulation could thus affect neuron production, neuronal migration, and overall cortical architecture; however, signaling mechanisms among radial glia have not been studied directly. We demonstrate here that calcium waves propagate through radial glial cells in the proliferative cortical ventricular zone (VZ). Radial glial calcium waves occur spontaneously and require connexin hemichannels, P2Y1 ATP receptors, and intracellular IP3-mediated calcium release. Furthermore, we show that wave disruption decreases VZ proliferation during the peak of embryonic neurogenesis. Taken together, these results demonstrate a radial glial signaling mechanism that may regulate cortical neuronal production.

Clinical Trials of Propentofylline in Vascular Dementia

Summary: The neuroprotective glial cell modulator propentofylline has been used in clinical trials involving more than 800 patients with vascular dementia (VaD). These data derive from two sources: a pooled group of VaD patients from four early phase III European trials, and a multinational European/Canadian phase III study (MN 305) that features a combined randomized withdrawal/delayed onset of progression design to evaluate the effect of propentofylline on disease progression. In the pooled studies, DSM-III-R criteria, Hachinski Ischemia Scores, computed tomography (CT), and magnetic resonance imaging (MRI) were used to select subjects with mild-to-moderate disease; in MN 305, National Institute of Neurological Disorders and Stroke/Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria and neurologic examinations (including CT and MRI scans) were used to select patients with possible or probable VaD. The use of a central rater to assess cerebrovascular disease in neuroradiologic examinations for study MN 305 was considered to be a key feature for reducing the heterogeneity of the VaD patient population. In addition, the inclusion of patients with possible VaD in this trial greatly increased the number of eligible patients; subgroup analyses revealed no substantial differences between patients with probable versus possible VaD, justifying their inclusion in the study. VaD patients exhibited a more pronounced placebo response in global assessments compared with the Alzheimer disease population in a parallel study. In addition, they experienced less deterioration over time with respect to cognitive and global assessments. Beneficial effects of propentofylline were consistently demonstrated in the domains of cognitive and global function for both VaD populations; however, no treatment benefits could be demonstrated for activities of daily living, possibly due to factors relating to the study population/design, the lack of a validated test instrument for such patients, the caregiver-related phenomenon of “tutoring,” or the nature of the disease itself.

Assessing the Societal Impact of Acetylcholinesterase Inhibitor Therapies

Summary: The symptomatology of Alzheimer disease (AD), its longevity, and associated cost make it an extremely challenging disease for individuals, their families, health care, and social support systems. Moreover, the expanding aging population worldwide means that strategies to contain costs are an urgent priority. As the largest component of the direct costs of AD is due to the cost of institutionalization, cost-containment strategies have focused on ways to maintain the AD patient in the community for as long as possible. Disease severity is a strong predictor of institutionalization, and patients' cognitive function (in the form of their Mini-Mental State Examination score) is frequently used as a prognostication of their living environment, and thus the overall cost of their care. Strategies to maintain patients at home are directed at either the patient's symptoms or the caregiver's ability to cope with those symptoms and the responsibilities of caregiving. Examples of strategies directed at the caregiver include education and support programs. Drug treatments, notably acetylcholinesterase inhibitors, present the best option for improving patient function, thereby preserving patient autonomy. A number of preliminary studies, whose results are summarized here, have demonstrated that the use of the acetylcholinesterase inhibitors tacrine, metrifonate and donepezil, and the glial cell modulator, propentofylline, results in reductions in the overall costs of care. Most health economic studies have focused only on comparison of the costs associated with paying for administering a treatment and the savings produced by postponed institutionalization. However, there is a growing realization that some measures of the quality of life or well-being of both patient and caregiver should also be incorporated. Thus, the health economics of dementia is an extremely complex area of study that is rapidly growing, due to the likelihood that cost-effectiveness will form the basis for future reimbursement decisions.

Assessing the Societal Impact of Acetylcholinesterase Inhibitor Therapies

The symptomatology of Alzheimer disease (AD), its longevity, and associated cost make it an extremely challenging disease for individuals, their families, health care, and social support systems. Moreover, the expanding aging population worldwide means that strategies to contain costs are an urgent priority. As the largest component of the direct costs of AD is due to the cost of institutionalization, cost-containment strategies have focused on ways to maintain the AD patient in the community for as long as possible. Disease severity is a strong predictor of institutionalization, and patients' cognitive function (in the form of their Mini-Mental State Examination score) is frequently used as a prognostication of their living environment, and thus the overall cost of their care. Strategies to maintain patients at home are directed at either the patient's symptoms or the caregiver's ability to cope with those symptoms and the responsibilities of caregiving. Examples of strategies directed at the caregiver include education and support programs. Drug treatments, notably acetylcholinesterase inhibitors, present the best option for improving patient function, thereby preserving patient autonomy. A number of preliminary studies, whose results are summarized here, have demonstrated that the use of the acetylcholinesterase inhibitors tacrine, metrifonate and donepezil, and the glial cell modulator, propentofylline, results in reductions in the overall costs of care. Most health economic studies have focused only on comparison of the costs associated with paying for administering a treatment and the savings produced by postponed institutionalization. However, there is a growing realization that some measures of the quality of life or well-being of both patient and caregiver should also be incorporated. Thus, the health economics of dementia is an extremely complex area of study that is rapidly growing, due to the likelihood that cost-effectiveness will form the basis for future reimbursement decisions.

Economic impact of introducing propentofylline for the treatment of dementia in Sweden

The purpose of this study was to estimate the impact of the introduction of propentofylline, a glial-cell modulator with neuroprotective properties, on the costs of dementia care in Sweden. To estimate the clinical effects of propentofylline treatment on dementia, we conducted a meta-analysis of four double-masked, placebo-controlled, randomized clinical trials and a simulation in a cohort of 57,000 patients with Alzheimer's disease (AD) or vascular dementia (VaD). This cohort represented the fraction of the total AD and VaD population in Sweden with mild-to-moderate disease, the target population for propentofylline treatment. The rate of progression of dementia was expressed in terms of the annual rate of change in score on the Mini—Mental State Examination (MMSE). The costs of care were estimated on the basis of a prospective population-based study. A regression model was used to quantify the costs of dementia care as a function of MMSE score. The estimates obtained were used to calculate and compare the costs of dementia care until death, with or without propentofylline treatment. The sensitivity of the results to a variety of model assumptions was also assessed. The total gross cost for 9 years under the current treatment strategy was SEK (Swedish kronor) 168.06 billion. Including propentofylline in the treatment strategy yielded net savings of SEK 0.8 billion, since the savings in the cost of patient care outweighed the drug acquisition costs. Over 9 years, this saving represents 3.8% of the costs of dementia care in the target population (MMSE score, 15–25 points) and 0.5% of the costs in the total AD and VaD population. The annual savings per patient ranged from SEK 5517 to 6387 during the first 4 years of propentofylline treatment. If an extended neuroprotective effect of propentofylline is assumed, savings increase to SEK 1.6 billion, equivalent to 7.6% of total care costs in the target population and 1.0% in the total population. Savings increase to SEK 14.6 billion if the extended neuroprotective effect is assumed to be effective in an extended target population (MMSE score, 0–25 points) without increased survival. In the sensitivity analysis, most scenarios yielded benefits in favor of propentofylline treatment. The clinical effects of propentofylline translate into meaningful economic effects. The drug acquisition costs are more than offset by the savings achieved in the cost of care. The inclusion of a broader range of outcomes may increase these savings.

Regional differences in glial cell modulation of synaptic transmission.

Metabolic integrity of glial cells in field CA1 of the guinea pig hippocampus is critical to maintenance of synaptic transmission (Keyser and Pellmar [1994] Glia 10:237-243). To determine if this tight glial-neuronal coupling is equally important in other brain regions, we compared the effect of fluoroacetate (FAC), a glial specific metabolic blocker, on synaptic transmission in field CA1 to synaptic transmission in area dentata (DG). FAC was significantly more effective in decreasing synaptic potentials in CA1 than in DG. A similar regional disparity in the FAC-induced decrease in ATP levels was evident. Isocitrate, a glial specific metabolic substrate, prevented the FAC-induced synaptic depression in both CA1 and DG. The results suggest that glia of CA1 and dentate respond differently to metabolic challenge. Modulation of this glial-neuronal coupling could provide a regionally specific mechanism for synaptic plasticity. Additionally, site-specific glial-neuronal interactions can impact on a variety of physiological and pathophysiological conditions.

Signal transduction and glial cell modulation of cultured brain microvessel endothelial cell tight junctions.

Noncontact coculture of postconfluent bovine brain microvessel endothelial cell (BMEC) monolayers with rat C6 glioma cells results in markedly decreased transmonolayer permeability measured by transendothelial electrical resistance (TER) and solute flux. An elevation in adenosine 3',5'-cyclic monophosphate (cAMP) in response to forskolin correlates with an increase in TER through a threshold event; however, unlike forskolin, the severalfold increase in TER induced by C6 cells is cAMP independent. Activation of protein kinase C (PKC) enhances the C6 cell-induced increase in TER, and PKC inhibition blocks C6 cell induction. Treatment of control or C6 cell-induced BMEC monolayers with pertussis toxin immediately and irreversibly obliterates TER, without an apparent change in guanosine 3',5'-cyclic monophosphate levels or viability, indicating the importance of a G protein-mediated event. A similar effect is observed with transforming growth factor-beta 1, and both responses are polarized, since the loss in TER is significantly faster in BMEC monolayers exposed basolaterally. These results suggest that astroglia modulate the blood-brain barrier through a cAMP-independent PKC-dependent pathway maintained by a G protein-coupled mechanism.

Sexual dimorphism and sex steroid modulation of glial fibrillary acidic protein messenger RNA and immunoreactivity levels in the rat hypothalamus

By using the techniques of in situ hybridization histochemistry and immunocytochemistry, we have found that both glial fibrillary acidic protein messenger RNA levels and glial fibrillary acidic protein immunoreactive surface density in the arcuate nucleus and median eminence are modulated by both the neonatal and adult sex steroid environments. No effect was seen on the number of immunoreactive glia. Intact adult males had significantly higher glial fibrillary acidic protein messenger RNA levels and glial fibrillary acidic protein immunoreactive surface density than females. Both adult and neonatal castration of male animals significantly reduced glial fibrillary acidic protein messenger RNA levels and glial fibrillary acidic protein immunoreactive surface density. Neonatal and adult testosterone treatment increased both of these parameters in both sexes; however, there was no additive effect of the steroid treatments. Glial cells are involved in the proliferation, survival, migration and maturation of neurons, as well as in the modulation of synaptic connectivity, and therefore it follows that hormonal modulation of glia may mediate some of the known steroid effects on neurons. The data reported here show that astroglia are significantly influenced by both the neonatal and adult sex steroid environments and suggest that some of the steroid effects on neurons during both of these developmental periods may be mediated, at least in part, through modulation of glial cells.