Synthesis and biological evaluation of Esaprazole analogues showing σ1 binding and neuroprotective properties in vitro.

Esaprazole, a molecule previously acknowledged to protect against stomach and intestinal ulcers was surprisingly discovered to have neuroprotective activities and σ1 binding in vitro. A highly diverse set of Esaprazole analogues 2-5 was prepared in order to increase blood-brain barrier penetration. The analogues showed a structure-activity relationship at the σ1 receptor closely matching already published pharmacophores. Many of the analogues were shown to have neuroprotective properties in two assays using primary cultures of cortical neurons exposed to glutamate and hydrogen peroxide. However, no apparent SAR for these two assays could be developed. Metabolic stability of the analogues were also investigated and the structure of R(1) had a significant bearing on the ADME properties of the compound resulting in two series of compounds. Compounds in which R(1) was a H or acyl group had good metabolic stability in RLM but poor BBB penetration, whereas compounds where R(1) was a cyclo- or bicyclo-alkyl group had poor metabolic stability but good BBB penetration.

Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses.

Lysosomal storage diseases (LSDs) often manifest with severe systemic and central nervous system (CNS) symptoms. The existing treatment options are limited and have no or only modest efficacy against neurological manifestations of disease. We demonstrate that recombinant human heat shock protein 70 (HSP70) improves the binding of several sphingolipid-degrading enzymes to their essential cofactor bis(monoacyl)glycerophosphate in vitro. HSP70 treatment reversed lysosomal pathology in primary fibroblasts from 14 patients with eight different LSDs. HSP70 penetrated effectively into murine tissues including the CNS and inhibited glycosphingolipid accumulation in murine models of Fabry disease (Gla(-/-)), Sandhoff disease (Hexb(-/-)), and Niemann-Pick disease type C (Npc1(-/-)) and attenuated a wide spectrum of disease-associated neurological symptoms in Hexb(-/-) and Npc1(-/-) mice. Oral administration of arimoclomol, a small-molecule coinducer of HSPs that is currently in clinical trials for Niemann-Pick disease type C (NPC), recapitulated the effects of recombinant human HSP70, suggesting that heat shock protein-based therapies merit clinical evaluation for treating LSDs.

Intravenous immunoglobulin ameliorates experimental autoimmune encephalomyelitis and reduces neuropathological abnormalities when administered prophylactically.

BACKGROUND AND METHODS: Immunomodulation with intravenous immunoglobulin (IVIG) represents a way of interfering with the disease process in multiple sclerosis (MS). In this study, the effects of IVIG on neurological symptoms and central nervous system (CNS) pathology were evaluated in experimental autoimmune encephalomyelitis (EAE), an MS animal model. EAE was induced in susceptible Dark Agouti rats by active immunization with a spinal cord homogenate, and infusions of 1 g/kg IVIG were given prophylactically or therapeutically. RESULTS: The administration of IVIG at the time of immunization significantly suppressed the development of neurological symptoms compared with infusions of placebo (mean EAE score 0.6+/-0.3 versus 2.3+/-0.4). Moreover, the prophylactic IVIG administration resulted in a significant inhibition of the inflammatory response in CNS tissue (inflammation score 1.1+/-0.2 versus 1.8+/-0.2 after placebo). No beneficial effects were obtained by therapeutic IVIG infusions as the EAE disease course and the degree of inflammation and demyelination in the CNS were not different from animals receiving treatment with placebo. CONCLUSIONS: The present study indicates that IVIG reduces the symptoms of EAE by suppression of the CNS inflammation that characterizes CNS pathology in these animals. Taking into account data from clinical trials of IVIG in MS, the results further suggest that IVIG acts primarily during the induction phase of the immune response thus preventing the development of relapses in MS.

IVIG enters the central nervous system during treatment of experimental autoimmune encephalomyelitis and is localised to inflammatory lesions.

Intravenous immunoglobulin (IVIG) treatment reduces the relapse rate in relapsing-remitting multiple sclerosis (MS) and may interfere with MS pathology through its various anti-inflammatory and immunomodulatory properties. It is presently unknown whether IVIG enters the central nervous system (CNS) in sufficient amounts to influence the local immune response within the brain and spinal cord, or if the treatment effects are entirely due to peripheral actions of IVIG. The purpose of the present study was to evaluate if IVIG radiolabeled with 99mTc enters the CNS during treatment of experimental autoimmune encephalomyelitis (EAE) in the susceptible rat strain Dark Agouti. After in vivo administration of 99mTc-IVIG we observed significantly increased accumulation in the brain and spinal cord from rats with EAE. Accumulation of 99mTc-IVIG was not detectable in CNS tissue from control animals. In peripheral tissue samples minor increases in 99mTc-IVIG organ binding were observed in the liver and kidney during EAE. Localisation of 99mTc-IVIG in the brain tissue was visualised by autoradiography and revealed significant accumulation of IVIG only in areas also affected by perivascular inflammation and leakage of serum proteins. In conclusion, the results indicate that significant extravasation of IVIG to the CNS only occurs when blood-brain barrier function is compromised during EAE.