Pattern of Injury with a Graded Excitotoxic Insult and Ensuing Chronic Medial Septal Damage in the Rat Brain

Abstract

Brain damage caused by an acute injury depends on the initial severity of the injury and the time elapsed after the injury. To determine whether these two variables activate common mechanisms, we compared the response of the rat medial septum to insult with a graded series of concentrations of a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) with the time-course effects of a low dose of AMPA. For this purpose we conducted a dose-response study at concentrations of AMPA between 0.27 and 10.8 nmol to measure atrophy of the septal area, losses of cholinergic and GABAergic neurons, astroglial and microglial reactions, and calcification. Cholinergic neurons, whose loss paralleled the degree of septal atrophy produced by AMPA, are more sensitive than GABAergic neurons to the injury produced by AMPA. At doses of AMPA above 2.7 nmol, calcification and the degree of microglial reaction increased only in the GABAergic region of the septal area, whereas atrophy and neuronal loss reached a plateau. We chose the 2.7-nmol dose of AMPA to determine how these parameters were modified between 4 days and 6 months after injection. We found that atrophy and neuronal loss increased progressively through the 6-month study period, whereas astrogliosis ceased to be observed after 1 month, and calcium precipitates were never detected. We conclude that septal damage does not increase with the intensity of an excitotoxic insult. Rather, it progresses continuously after the insult. Because these two situations involve different mechanisms, short-term paradigms are inappropriate for interpreting the pathogenic mechanisms responsible for long-term neurodegenerative processes.

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

“…In close contact with the nucleus, which also produces ATP from the ADP-ribosyl residues after sudden extensive changes in chromatin [99] (perhaps the ones caused by the heterogeneous ribonucleoproteins (hnRNPs) identified in ALS) proteasome becomes especially important for maintaining cellular homeostasis through degradation of ubiquitinated factors like Drp1, which control mitochondria fusion and fission and the ubiquitinated misfolded ALS proteins [100]. In addition, reduced glucose uptake and metabolism consequent to increased glucocorticoid signaling pathways cannot be discarded [101][102][103].…”

The L-type voltage-gated calcium channel modulates microglial pro-inflammatory activity

“…Briefly, sections were incubated overnight at 4 ºC with IB4 diluted 1:25 in normal goat serum (NGS, 1:100 v/v in 0.01 M PBS; pH 7.4). Immunohistochemistry was carried out in consecutive sections with the avidin-biotin peroxidase method as previously described (Rodríguez et al, 2009a). The L-type VGCC was labeled The hippocampal size and the area occupied by the neural loss were measured on Nissl stained sections using a computer-assisted image analysis system (Image-Pro Plus, Media Cybernetics Inc., MD, USA).…”

Microglia, Calcification and Neurodegenerative Diseases

“…As such, several different CNS disorders can be induced following the same injury, due to the multi-directional interactions between the neurons, glial cells, extracellular matrix, endothelia and host immune cells that regulate tissue homeostasis and orchestrate neuroinflammation and degeneration. Furthermore, the characteristics of each neuronal population and network, the different gliopathic changes occurring between CNS areas, the various microglia phenotypes and the abundance and distribution of glutamate receptor subtypes and of Ca 2+ -binding proteins, all participate directly in the properties of the neurodegenerative parameters (Graeber & Streit, 2010, Rodriguez et al, 2004, Rodriguez et al, 2009a) that will determine the dynamics and progression of the disease in the specific affected areas. For example, PD and AD are both regarded as diseases that are initiated by neuronal death to which the immune system responds, as evidenced by astroglial and microglial activation with pathogenic consequences (Agostinho et al, 2010, Halliday & Stevens, 2011.…”

“…For example, microgliosis is associated with atypical and insoluble components caused by irregular protein folding and degradation pathways, altered subcellular localization, and the abnormal interactions with other cellular proteins found in AD, PD HD, Down syndrome and normal aging. Microgliosis is also associated with the formation of extracellular ionic precipitates, such as hydroxyapatites, which are frequently observed within the CNS areas involved in the disease (Rodriguez et al, 2009a, Saura et al, 1995, and is also present in encephalopathies caused by prions. This innate immune response is currently considered to be a potential pathogenic factor, since microglial reaction may engender neurodegenerative events, including amyloid-beta plaque formation, dystrophic neurite growth, and excessive tau phosphorylation.…”

“…For example, astrocyte dysfunction is a key factor in the pathogenesis of human neurological disorders (Seifert et al, 2006), and in the cognitive impairment of aged rats (Andrés et al, 2000). Furthermore, glutamate-induced chronic lesion in rat brain not only presents a lack of astrogliosis but also long term atrophy of astrocytes, suggesting a maladaptive response that may be a cause of the on-going pathologic process (Rodriguez et al, 2009a). Moreover, astrocytes influence microglial behaviour (figure 1).…”