Glycogen synthase kinase 3: a drug target for CNS therapiesBhat, Ratan V.; Budd Haeberlein, Samantha L.; Avila, Jesús
doi: 10.1111/j.1471-4159.2004.02422.xpmid: 15189333
Glycogen synthase kinase3 (GSK3) is emerging as a prominent drug target in the CNS. The most exciting of the possibilities of GSK3 lies within the treatment of Alzheimer's disease (AD) where abnormal increases in GSK3 levels and activity have been associated with neuronal death, paired helical filament tau formation and neurite retraction as well as a decline in cognitive performance. Abnormal activity of GSK3 is also implicated in stroke. Lithium, a widely used drug for affective disorders, inhibits GSK3 at therapeutically relevant concentrations. Thus while the rationale remains testable, pharmaceutical companies are investing in finding a selective inhibitor of GSK3. In the present review, we summarize the properties of GSK3, and discuss the potential for such a therapy in AD, and other CNS disorders.
Could a loss of α‐synuclein function put dopaminergic neurons at risk?Perez, Ruth G.; Hastings, Teresa G.
doi: 10.1111/j.1471-4159.2004.02423.xpmid: 15189334
The α‐synuclein gene is implicated in Parkinson's disease, the symptoms of which occur after a marked loss of substantia nigra dopamine neurons. While the function of α‐synuclein is not entirely elucidated, one function appears to be as a normal regulatory protein that can bind to and inhibit tyrosine hydroxylase, the rate‐limiting enzyme in dopamine synthesis. Soluble α‐synuclein levels may be diminished in Parkinson's disease substantia nigra dopamine neurons both by reduced expression and by α‐synuclein aggregation as Lewy bodies and Lewy neurites form. The loss of functional α‐synuclein may then result in dysregulation of tyrosine hydroxylase, dopamine transport and dopamine storage, resulting in excess cytosolic dopamine. Because dopamine and its metabolites are reactive molecules capable of generating highly reactive quinones and reactive oxygen species, a failure to package dopamine into vesicles could cause irreversible damage to cellular macromolecules and contribute to resultant neurotoxicity. This review focuses on how a loss of normal α‐synuclein function may contribute to the dopamine‐related loss of substantia nigra neurons during Parkinson's disease pathogenesis.
Focal dysfunction of the proteasome: a pathogenic factor in a mouse model of amyotrophic lateral sclerosisKabashi, Edor; Agar, Jeffrey N.; Taylor, David M.; Minotti, Sandra; Durham, Heather D.
doi: 10.1111/j.1471-4159.2004.02453.xpmid: 15189335
Mutations in the Cu/Zn‐superoxide dismutase (SOD‐1) gene are responsible for a familial form of amyotrophic lateral sclerosis (fALS). The present study demonstrated impaired proteasomal function in the lumbar spinal cord of transgenic mice expressing human SOD‐1 with the ALS‐causing mutation G93A (SOD‐1G93A) compared to non‐transgenic littermates (LM) and SOD‐1WT transgenic mice. Chymotrypsin‐like activity was decreased as early as 45 days of age. By 75 days, chymotrypsin‐, trypsin‐, and caspase‐like activities of the proteasome were impaired, at about 50% of control activity in lumbar spinal cord, but unchanged in thoracic spinal cord and liver. Both total and specific activities of the proteasome were reduced to a similar extent, indicating that a change in proteasome function, rather than a decrease in proteasome levels, had occurred. Similar decreases of total and specific activities of the proteasome were observed in NIH 3T3 cell lines expressing fALS mutants SOD‐1G93A and SOD‐1G41S, but not in SOD‐1WT controls. Although overall levels of proteasome were maintained in spinal cord of SOD‐1G93A transgenic mice, the level of 20S proteasome was substantially reduced in lumbar spinal motor neurons relative to the surrounding neuropil. It is concluded that impairment of the proteasome is an early event and contributes to ALS pathogenesis.
A novel lipopolysaccharide‐modulated Jun binding repressor in intron 2 of CYP2E1Tindberg, Niclas; Bengtsson, Inger; Hu, Yin
doi: 10.1111/j.1471-4159.2004.02449.xpmid: 15189336
Cytochrome P450 2E1 (CYP2E1) exhibits a pronounced oxidase activity that may mediate apoptotic injury in glial cells as well as hepatocytes. Strict regulation of CYP2E1 and it's activity is therefore thought to be crucial. We have studied CYP2E1 transcriptional regulation in primary cortical glial cells and have identified a novel repressor element at +1452/+1460 in intron 2 of the rat CYP2E1 gene. The element very potently repressed CYP2E1 and SV40 promoters and consisted of the non‐palindromic core sequence 5′‐TTCCACTCA‐3′. Jun proteins were found to interact with the site. The protein complexes were also found to contain an as yet unidentified protein of ≈60 kDa, probably with DNA binding properties similar to G‐box binding factors found in, e.g. Arabidopsis thaliana. Stimulation with lipopolysaccharide, or overexpression of the mitogen‐activated protein kinase kinase kinase, MEKK‐1, further deepened the repression in primary cortical glial cells. It is suggested that this novel Jun binding repressor helps to control basal expression levels of CYP2E1, and modulates the response to inflammatory factors. Future in vivo experiments will, however, be required for a full appreciation of the role of this repressor in the complex regulation of CYP2E1 during inflammatory conditions.
Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat shock protein inductionRen, Ming; Leng, Yan; Jeong, MiRa; Leeds, Peter R.; Chuang, De‐Maw
doi: 10.1111/j.1471-4159.2004.02406.xpmid: 15189338
Growing evidence from in vitro studies supports that valproic acid (VPA), an anti‐convulsant and mood‐stabilizing drug, has neuroprotective effects. The present study investigated whether VPA reduces brain damage and improves functional outcome in a transient focal cerebral ischemia model of rats. Subcutaneous injection of VPA (300 mg/kg) immediately after ischemia followed by repeated injections every 12 h, was found to markedly decrease infarct size and reduce ischemia‐induced neurological deficit scores measured at 24 and 48 h after ischemic onset. VPA treatment also suppressed ischemia‐induced neuronal caspase‐3 activation in the cerebral cortex. VPA treatments resulted in a time‐dependent increase in acetylated histone H3 levels in the cortex and striatum of both ipsilateral and contralateral brain hemispheres of middle cerebral artery occlusion (MCAO) rats, as well as in these brain areas of normal, non‐surgical rats, supporting the in vitro finding that VPA is a histone deacetylase (HDAC) inhibitor. Similarly, heat shock protein 70 (HSP70) levels were time‐dependently up‐regulated by VPA in the cortex and striatum of both ipsilateral and contralateral sides of MCAO rats and in these brain areas of normal rats. Altogether, our results demonstrate that VPA is neuroprotective in the cerebral ischemia model and suggest that the protection mechanisms may involve HDAC inhibition and HSP induction.
Alterations in hippocampal phospholipid profile by prenatal exposure to ethanolWen, Zhiming; Kim, Hee‐Yong
doi: 10.1111/j.1471-4159.2004.02433.xpmid: 15189339
It has been suggested that hippocampus‐related cognitive processes are especially sensitive to ethanol. To provide an insight into the biochemical mechanisms underlying the hippocampus‐related functional deficits associated with prenatal ethanol exposure, we investigated the effects of chronic ethanol exposure on the phospholipid profile in developing rat hippocampi. High‐performance liquid chromatography/electrospray ionization–mass spectrometry analysis revealed that ethanol lowered the levels of total phosphatidylserine (PS) by 15–20% at all ages examined, primarily owing to the reduction in 1‐stearoyl‐2‐docosahexaenoyl‐PS (18:0,22:6n‐3‐PS) species. Ethanol exposure also led to a decrease in phosphatidylcholine (PC) and an increase in phosphatidylethanolamine (PE), but the total phospholipid content was not significantly changed. At the fatty acid level, ethanol exposure significantly decreased the 22:6n‐3 content at postnatal days 0 and 21, with a slight increase in 22:5n‐6, without changing the total fatty acid content significantly. In conclusion, ethanol depleted PS, especially 22:6‐containing species, and PC from hippocampal membranes with concomitant increase in PE. Alteration of the phospholipid profile in the hippocampus resulting from exposure to ethanol during prenatal and developmental stages may have significant implications with respect to the cognitive dysfunction observed in fetal alcohol syndrome.
Reduction of excitotoxicity and associated leukocyte recruitment by a broad‐spectrum matrix metalloproteinase inhibitorCampbell, Sandra J.; Finlay, Malcolm; Clements, John M.; Wells, Graham; Miller, Karen M.; Perry, V. Hugh; Anthony, Daniel C.
doi: 10.1111/j.1471-4159.2004.02441.xpmid: 15189340
An important step in the cascade leading to neuronal cell death is degradation of laminin and other components of the brain extracellular matrix by microglia‐derived proteases. Excitotoxic cell death of murine hippocampal neurones in vivo can be prevented by inhibitors of tissue plasminogen activator (tPA) or by inhibitors of plasmin. Plasmin is a potent activator of the matrix metalloproteinases (MMPs), which are made by resident and recruited leukocytes following CNS injury. In this study, we show, using Taqman RT‐PCR, that MMP mRNAs, but not other calcium‐dependent proteases such as calpain mRNAs, are acutely up‐regulated after an excitotoxic challenge in vivo. α2‐antiplasmin or BB‐3103, a broad‐spectrum inhibitor of the MMPs, co‐injected with kainic acid into the striatum, inhibits excitotoxic cell death in the rat striatum, and reduces both the number of recruited macrophages and the size of the lesion. We also show that leukocyte populations differentially express MMPs, which may account, in part, for the expression profile we observe in the challenged brain. Our results show that inhibition of the MMPs in the rat will prevent kainic acid‐induced cell death in the brain. These studies suggest that MMP inhibitors have therapeutic potential for use in stroke, and support the increasing evidence that microglial activation may contribute to neuronal cell death.
A non‐peptidyl neurotrophic small molecule for midbrain dopaminergic neuronsLin, Leu‐Fen H.; Rubin, Lee L.; Xu, Mei
doi: 10.1111/j.1471-4159.2004.02412.xpmid: 15189341
A small organic molecule (CUR‐162590) that selectively enhances survival of midbrain dopaminergic neurons was identified by screening small molecule compound libraries. In embryonic midbrain cultures, CUR‐162590 increased dopamine uptake and the number of dopaminergic neurons without altering the number of total neurons or astroglia or the uptake of GABA or serotonin. CUR‐162590 reduced apoptosis of cultured dopaminergic neurons and protected against death induced by toxins such as MPP+. Several synthetic analogs of CUR‐162590 also had similar bioactivities. CUR‐162590 thus represents a new class of neurotrophic small molecules that may have utility in the treatment of Parkinson's disease, which is marked by degeneration of midbrain dopaminergic neurons.