Memantine is effective for dementia; animal model studies.
The following are abstracts papers presented at the International Conference on Alzheimer's Disease and related disorder 6th International Conference on Alzheimer's Disease and related disorder July 18 - 23, 1998; Amsterdam, the Netherlands.
These are nice demonstrations from animal models of the neuroprotective effects of memantine. They provide a glimpse of the mechanism by which NTII's memantine produces its significant clinical benefit.
John de C
Protection by memantine against A-Beta(1-40)-induced neurodegeneration in the CA1 subfield
Male Sprague-Dawley rats (250-275 g) were injected into the CA1 hippocampal region with b-Amyloid fragment 1-40 or 2 ml distilled water. Two days before this injection, rats were implanted with Alzet osmotic minipumps delivering the uncompetitive NMDA-receptor antagonist memantine (15 mg/kg/day) or distilled water for a total of nine days. Treatment with memantine led to steady state plasma concentrations between 1.40 and 3.58 mM. The rats' brains were fixed by perfusion, extracted out, embedded in paraffin and sectioned. Hippocampal sections were stained with Congo Red-Haematoxylin or processed for immunohistochemistry of glial-fibrillary acidic protein (GFAP), ED1 antibody for activated microglia, microtubule-associated protein 2 (MAP2) and b-amyloid protein. We found that the treatment with memantine reduced significantly the extension of the b-amyloid-induced lesion in the CA1 subfield and that there was a tendency for a reduced lesion in the gyrus dentatus. There was also a significant reduction of the area occupied by GFAP-positive hypertrophic astrocytes in the lesioned hippocampus, a decrease in the labeling of activated microglia with antibody ED1 and a diminution of MAP2-positive neuronal somata in the CA1 subfield. One day before the sacrifice the same animals employed for the morphological and histochemical studies were subjected to behavioral testing for psychomotor activity, psychomotor coordination (Rota-Rod), passive avoidance learning and spatial discriminative learning (T-maze). In the passive avoidance testing, a significant increase in the number of avoidances (p < 0.05) and in mean latency per trial (p < 0.01) from the acquisition to the retention session was observed in rats treated with memantine, but not in control lesioned animals. There were no differences in psychomotor activity, psychomotor coordination or spatial discrimination. Memantine displays neuroprotective effects in the present model of degeneration and might be useful for the treatment of neurodegenerative disorders such as Alzheimer's disease and other dementias.
Potential therapies for a novel animal model of Alzheimer's Disease - Chronic neuroinflammation of transgenic rats that overexpress human Beta-amyloid
It is not yet known whether brain inflammation alone is sufficient to induce the pathophysiological changes and cognitive impairments seen in Alzheimer's Disease (AD). In the present study, we investigated the biochemical, histopathological and behavioral consequences of chronic brain infusion of a proinflammatory agent, lipopolysaccharide (LPS), into the 4th ventricle of young rats. We also investigated whether the combined presence of chronic neuroinflammation and overexpression of human b-amyloid can produce neuropathological changes that resemble those seen in AD. Briefly, normal or transgenic "Abeta overexpressing" rats had a cannula implanted into their 4th ventricle that was connected to an osmotic mini-pump(Alzet 2002). LPS (1 mg/ml) or artificial CSF were infused for 4 weeks. LPS-treated transgenic rats showed a spatial memory deficit. Immunocytochemical (ICC) staining for the MHC-II class antigens revealed numerous activated microglia primarily within temporal lobe regions. Under these conditions, neuronal death occurred in the dorsal hippocampus. Silver impregnation staining revealed numerous densely packed, argyrophilic structures that were characterized by an inhomogeneous dark staining of scattered, somewhat tortuous neurites of variable density. The parietal and temporal cortexes contained the greatest concentration of these structures. None of these darkly stained structures was seen in aCSF-treated transgenic or non-transgenic rats. Chronic LPS infusions also resulted in a 3-fold induction of IL-1b, APOE, and IL-1a mRNA in selected brain regions. The LPS infusion produced a 3-fold induction in mRNA levels for TNFa, amyloid precursor protein and GFAP in the basal forebrain, but not in hippocampus. Chronic treatment with an anti-inflammatory drug attenuated many of these effects. Chronic treatment with the uncompetitive NMDA receptor antagonist memantine (20 mg/kg/d, i.p.) significantly attenuated the loss of basal forebrain cholinergic cells induced by an LPS infusion. Supported by Merz + Co and the Alzheimer's Association IIRG-95-004. |
