title: 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 alpha-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.
authors.affiliation: Unitat de Bioquímica, Ginecologia, Pedriatria, Radiologia i Medicina Funcional, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain. marodriguez@ub.edu
authors.forename: Manuel J
authors.initials: MJ
authors.lastname: Rodríguez
authors.forename: Alberto
authors.initials: A
authors.lastname: Prats
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Malpesa
authors.forename: Noemí
authors.initials: N
authors.lastname: Andrés
authors.forename: Marco
authors.initials: M
authors.lastname: Pugliese
authors.forename: Montserrat
authors.initials: M
authors.lastname: Batlle
authors.forename: Nicole
authors.initials: N
authors.lastname: Mahy
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001284:Atrophy / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D001925:Brain Damage, Chronic / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005911:Gliosis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012686:Septal Nuclei / Q000473:pathology / Q000503:physiopathology*; D013995:Time; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018690:Excitatory Amino Acid Agonists; D009498:Neurotoxins; D005680:gamma-Aminobutyric Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D000109:Acetylcholine