Neurodegeneration最新文献

No abstract

The apparent existence of multiple strains of the «transmissible agent» associated with spongiform encephalopathy (prion disease) has been used to support the argument that these diseases are caused by an independent, replicating agent with its own genome. However, the length of the incubation period (time from injection of infected material to onset of clinical signs) and the lesion profile (regional distribution of neuropathology), which are the key features used to define the strain of agent, have been shown to be influenced by the prion protein of the host and the donor, such that it is only the variance in these measures which remains after variation due to all other factors has been taken into account, which can be used as evidence for the existence of different strains of agent. The donor is the animal from which infectious material is prepared for injection into the host. Almost all aspects of pathogenesis, including most of the variance in incubation time, can be explained in terms of interactions between donor and host prion protein. We argue that the number of separate strains of agent may be more limited than is usually represented. It is important to distinguish between the hypothesis that the prion protein of the host «permits» the selection of mutated strains and the hypothesis that it «induces» changes in the agent. The former is consistent with the concept of an agent with an independent genome while the latter is consistent with the concept that «strain of agent» is another expression of the involvement of prion protein in the pathogenesis of transmissible spongiform encephalopathy.

Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6Ndash;tetrahydropyridine or 1-methyl-4-phenylpyridinium (MPP⁺) are potential endogenous neurotoxins causing nigral cell death in Parkinson's disease. We now report the effects of 7 days unilateral supranigral infusion in rats of four isoquinoline derivatives, namely N-n-propylisoquinolinium (N-Pr-IQ⁺), N-methyl-6,7-dimethoxyisoquinolinium (N-Me-6,7-diOMe-IQ⁺), 6,7-dimethoxy-1-styrylNdash;3,4-dihydroisoquinoline (6,7-diOMe-1-S-3,4-DHIQ) and 1,2,3,4-tetrahydroisoquinoline (THIQ) compared to MPP⁺. MPP⁺(33 nmol/24 h)-infused rats showed a marked reduction in motor activity and displayed ipsilateral postural asymmetry. Administration of apomorphine or (+)-amphetamine to these animals produced robust contralateral and ipsilateral rotations, respectively. In contrast, rats infused with the isoquinoline derivatives (150 nmol/24 h) did not show spontaneous or drug-induced motor changes. Infusion of MPP⁺decreased the number of tyrosine hydroxylase (TH)-positive cells in the ipsilateral substantia nigra pars compacta (SNc) by approximately 90%. Infusion of N–Me-diOMe-IQ⁺and THIQ produced approximately 42% and 20% ipsilateral SNc cell loss, respectively, but N-Pr-IQ⁺and 6,7-diOMe-1-S-3,4-DHIQ did not alter SNc cell numbers. MPP⁺markedly depleted the dopamine (DA, 95%), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) content of the ipsilateral striatum. N-Me-diOMe-IQ⁺and THIQ also reduced the DA content of the ipsilateral striatum by approximately 39% and 20% respectively, but N-Pr-IQ⁺and 6,7-diOMe-1-S-3,4-DHIQ did not deplete striatal DA content. The isoquinoline derivatives slightly reduced (N-Me-diOMe-IQ⁺and THIQ) or had no effect (N-Pr-IQ⁺and 6,7-diOMe-1-S-3,4-DHIQ) on DOPAC or HVA levels. In conclusion, some isoquinoline derivatives that are substrates for the dopamine re-uptake system and inhibitors of mitochondrial function, are toxic to nigral dopaminergic neurones. Chronic exposure to endogenous or exogenous isoquinoline derivatives might contribute to cell death in Parkinson's disease.

Some mice infected with murine leukaemia retrovirus, LP-BM5 including ecotropic, mink cell focus-inducing murine leukaemia virus, and a replication-defective genome, have been reported to show weakness, ataxia, or selective deficits in spatial learning after developing an immuno-deficiency syndrome similar to human AIDS. In the central nervous system, astrocytes and microglial cells have been shown to be infected by this virus. We present here findings that the ecotropic virus and defective genome can infect murine brain capillary endothelial cells, and infected endothelial cells show an impaired function as target cells against myelin basic protein (MBP) specific T cell clone.

The present study offers confirmation of the fact that an MAO—B inhibitor, (−) deprenyl and a DA uptake blocker, GBR—12909, prevent MPTP-induced striatal DA decrease. This protective effect is accompanied by an almost complete prevention of MPP⁺production induced by (−) deprenyl and an accelerated MPP⁺clearance induced by GBR—12909 within the striatum. Similarly, the MPTP toxicity enhancers, DDC and acetaldehyde, both increase striatal MPP⁺levels, as previously reported. On the contrary, the treatment with MK 801, although uneffective in preventing the long-term MPTP-induced striatal DA decrease, causes an increase in the striatal amount of MPP⁺. In a similar way, the administration of nicotine in combination with MPTP produces a significant increase in the levels of striatal MPP⁺, which does not elicit any effect on striatal DA. The effect of clonidine is consistent with these results and in sharp contrast with the current belief that a direct relationship exists between striatal MPP⁺concentrations and the degree of MPTP-induced depletion of striatal DA. In this study, using different treatments, we failed to confirm the correlation between MPP⁺striatal levels and dopaminergic lesions after MPTP administration in mice. We suggest that this correlation is not a rule and exceptions may depend on a different compartimentalization of the toxic metabolite.

Rats were treated for 28 days with increasing doses of dexfenfluramine (0.5, 1, 1.5, 2, 3, 4 and 5 mg/kg bid ip, each dose given for 4 days before being increased) and subsequently studied at intervals between 1 and 60 days following the cessation of treatment. Control rats received vehicle and were allowed foodad libitumor were pair fed with dexfenfluramine-treated animals. Immediately following drug treatment 5-HT immunoreactivity was increased in cortical areas compared to control animals. Subsequently, there was a persistent decrease in fine fibre density and the appearance of coarse truncated fibres. 5-HT levels in cortex were decreased 1 day following dexfenfluramine treatment but recovered to control values by 15 days. GFAP and GAP 43 immunoreactivity was unaffected by dexfenfluramine treatment compared to control animals, indicating a lack of evidence for neuronal degeneration and regeneration. Dexfenfluramine treatment decreased the density of 5-HT uptake sites in the cortex, labelled with [³H]-citalopram, but this partially recovered towards control values at 60 days. These alterations in 5-HT terminal networks conflict with the return of 5-HT levels to normal and the lack of evidence for degenerative changes or neuronal regrowth. On the basis of these results, it cannot be concluded that dexfenfluramine is neurotoxic.

The diffuse amyloid (Aβ) plaques of the cerebellum and corpus striatum were examined in 32 patients with Down's syndrome, ranging in age from 9 to 71 years, using the end-specific monoclonal antibodies BA27 and BC05 to detect Aβ species terminating at amino acids 40 and 42(43) respectively. When present, the diffuse plaques of both regions contained only Aβ₄₂₍₄₃₎at all ages. Aβ₄₀was, however, present along with Aβ₄₂₍₄₃₎in the few cored plaques that were occasionally present in the Purkinje and molecular cell layers of the cerebellum of some of the more elderly patients. It is concluded that diffuse plaques of the cerebellum and striatum contain only Aβ₄₂₍₄₃₎and that, in contrast to those of the cerebral cortex, these do not ‘mature’ during their lifetime into Aβ₄₀containing plaques.

Neuroprotection against excitotoxicity by a combined therapy with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and the L-type Ca²⁺channel blocker nimodipine was examined using an in vivo rat model of NMDA-induced neurodegeneration. Attention was focused on the neuroprotective potential of this combined drug treatmentbeforeandafterNMDA-exposure. NMDA was unilaterally injected in the magnocellular nucleus basalis (MBN). Neuronal damage was assessed 12 days after the NMDA-injection by measuring the reduction of cholinergic cortical fibres that originate from the MBN neurons. In controls that received no drug treatment, NMDA-exposure damaged MBN neurons such that 66% of the cholinergic terminals were lost in the ipsilateral parietal cortex. Pretreatment with a nimodipine diet (860 ppm) combined with application of MK-801 (5 mg/kg i.p.)beforeNMDA-exposure reduced fibre loss by 89% thereby providing a near complete neuroprotection. Combined therapy of MK-801 (5 mg/kg i.p.) and nimodipine (15 mg/kg i.p.) 8 minafterNMDA-infusion reduced neuronal injury by 82%, while the same combination given 2 hafterthe excitotoxic treatment still yielded a 66% protection against neurotoxic damage invoked by NMDA. In conclusion, the present data show that a dual blockade of NMDA-channels and voltage-dependent calcium channels (VDCC's) up to 2 h after NMDA-exposure is able to provide a significant protection against NMDA-neurotoxicity.

We used immunoblotting and radioligand binding techniques to compare levels of the calcium-mobilizing receptor for the phosphoinositide hydrolysis-derived intracellular second messenger inositol (1,4,5)-trisphosphate (IP₃) in post mortem samples from the temporal, frontal and parietal cortices of eight Alzheimer's disease (AD) and eight matched control cases. Immunoblotting with an antibody directed against the C-terminal end of the rat type I IP₃-receptor showed that IP₃-receptor protein levels were significantly reduced in the temporal (to 59 ± 6% of controls,P= 0.0002) and frontal (to 62 ± 10% of controls,P= 0.04), but not in the parietal cortices (to 63 ± 13% of controls,P= 0.1) of the AD cases, compared to controls. The number of [³H]IP₃radioligand binding sites was significantly decreased in the temporal cortex, but not frontal and parietal cortices, of the AD brains. The decreased levels of both immunoreactive IP₃-receptor protein and [³H]IP₃binding in the temporal cortex correlated with a semi-quantitative score for the severity of AD neuropathology. No significant changes were seen in the levels of glial fibrillary acidic protein, synaptophysin or phosphate-activated glutaminase, as markers for astrocytes, neuronal vesicles and mitochondria, respectively. It is concluded that in affected AD brain regions, the IP₃-receptor may represent a sensitive target for proteolysis, possibly mediated by activation of the Ca²⁺-activated neutral protease calpain. These degenerative changes may in part be responsible for the disruption of Ca²⁺homeostasis in AD-sensitive neurons.

The role of (−) deprenyl in offering neuroprotection to cortical neurons exposed to Aluminium chloride (AlCl₃) was examined. Primary cortical cultures derived from newborn rats were exposed to AlCl₃on 6th dayin vitro, at 100, 200, 400, 600, 800 and 1000 μM concentrations of AlCl₃. After 48 h of AlCl₃exposure, many nerve cell bodies were swollen; a beading of neurites and a disruption of the neuritic network were also observed suggesting neurodegeneration. Lactate dehydrogenase (LDH) efflux increased in a dose-dependent manner (59–120%). (−) Deprenyl co-exposure at concentrations of 10⁻⁷, 10⁻⁸and 10⁻⁹M significantly attenuated both the morphological alterations and the LDH efflux induced by AlCl₃. Thisin vitrostudy has demonstrated that (−) deprenyl can protect neurons from aluminium induced neurotoxicity.