Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes.

Strong epidemiologic evidence suggests an association between Alzheimer disease (AD) and type 2 diabetes. To determine if amyloid beta (Abeta) and hyperphosphorylated tau occurs in type 2 diabetes, pancreas tissues from 21 autopsy cases (10 type 2 diabetes and 11 controls) were analyzed. APP and tau mRNAs were identified in human pancreas and in cultured insulinoma beta cells (INS-1) by RT-PCR. Prominent APP and tau bands were detected by Western blotting in pancreatic extracts. Aggregated Abeta, hyperphosphorylated tau, ubiquitin, apolipoprotein E, apolipoprotein(a), IB1/JIP-1 and JNK1 were detected in Langerhans islets in type 2 diabetic patients. Abeta was co-localized with amylin in islet amyloid deposits. In situ beta sheet formation of islet amyloid deposits was shown by infrared microspectroscopy (SIRMS). LPS increased APP in non-neuronal cells as well. We conclude that Abeta deposits and hyperphosphorylated tau are also associated with type 2 diabetes, highlighting common pathogenetic features in neurodegenerative disorders, including AD and type 2 diabetes and suggesting that Abeta deposits and hyperphosphorylated tau may also occur in other organs than the brain

Hydrogen Sulfide-Releasing NSAIDs Attenuate Neuroinflammation Induced by Microglial and Astrocytic Activation

Endogenously generated hydrogen sulfide (H(2)S) may have multiple functions in brain. It has been shown that H(2)S attenuates the expression of pro-inflammatory cytokines by lipopolysaccharide (LPS)-activated microglia. Here we demonstrate a neuroprotective effect of NaSH and three H(2)S-releasing compounds, ADT-OH, S-diclofenac, and S-aspirin. When activated by LPS and gamma-interferon, human microglia and THP-1 cells release materials that are toxic to human neuroblastoma SH-SY5Y cells. These phenomena also occur with gamma-interferon-stimulated human astroglia and U118 cells. When these cell types are pretreated with aspirin, diclofenac, NASH, or ADT-OH, the supernatants are significantly less toxic. When they are treated with the NSAID-H(2)S hybrid molecules S-diclofenac and S-aspirin, which are here referred to as S-NSAIDs, there is a significant enhancement of the protection. The effect is concentration and incubation time dependent. Such pretreatment also reduces the release of the proinflammatory mediators TNFalpha, IL-6, and nitric oxide. The H(2)S-releasing compounds are without effect when applied directly to SH-SY5Y cells. These data suggest that hybrid H(2)S releasing compounds have significant antiinflammatory properties and may be candidates for treating neurodegenerative disorders that have a prominent neuroinflammatory component such as Alzheimer disease and Parkinson diseas

Novel neuroprotective hydrogen sulfide-releasing L-DOPA derivatives for the treatment of Parkinson disease

The main lesion in Parkinson disease (PD) is loss of substantia nigra dopaminergic neurons. Levodopa (L-DOPA) is the most widely used therapy but it does not arrest disease progression. Some possible contributing factors to the continuing neuronal loss are oxidative stress, including oxidation of L-DOPA, and neurotoxins generated by locally activated microglia and astrocytes. A possible method of reducing these factors is to produce L-DOPA hybrid compounds that have antioxidant and anti-inflammatory properties. Here we describe the syntheses and the properties of four such L-DOPA hybrids based on coupling L-DOPA methyl ester to four different hydrogen sulfide donating compounds, which were shown to be capable of conversion by isolated mitochondria to H2S or equivalent SH- ions; other hybrids are in development. This capability was confirmed by in vivo results, showing a large increase in intracerebral dopamine and glutathione after iv administration in rats. The H2S-releasing L-DOPA hybrid molecules also inhibited MAO B activity. When human microglia, astrocytes and SH-SY5Y neuroblastoma cells were treated with these donating agents, they all accumulated H2S intracellularly as did their derivatives coupled to L-DOPA. The donating agents and the L-DOPA hybrids reduced the release of tumor necrosis factor-\u3b1 and interleukin-6 from stimulated microglia, astrocytes as well as the THP-1 and U373 cell lines. They also demonstrated a neuroprotective effect by reducing the toxicity of supernatants from these stimulated cells to SH-SY5Y cells. L-DOPA itself was without effect in any of these assays. The significant antiinflammatory, antioxidant and neuroprotective properties of these new compounds make them potentially useful agents for the treatment of PD

H2S-releasing L-DOPA derivatives for Parkinson disease

L-DOPA is the most widely used therapy for Parkinson disease but it does not arrest progression of the disorder. Factors that contribute to the continuing neuronal loss are oxidative stress, including oxidation of L-DOPA, and neurotoxins generated by locally activated microglia and astrocytes. A possible method of reducing these factors is to produce L-DOPA hybrid compounds that have antioxidant and antiinflammatory properties. We have prepared four such L-DOPA hybrids, based on coupling L-DOPA to different hydrogen sulfide donating compounds. They show promise as disease modifying agents. This capability was demonstrated by in vivo results with one of the hybrids where larger increases in brain dopamine levels were observed than with equivalent doses of L-DOPA. The H2S-releasing L-DOPA hybrid molecules also inhibited MAO B activity which could explain why they increased dopamine levels in vivo. The donors themselves were shown to be capable of conversion to H2S or equivalent SH- ions by isolated mitochondria. When human microglia, astrocytes and SH-SY5Y neuroblastoma cells were treated with these donating agents, they all accumulated H2S intracellularly as did their derivatives coupled to L-DOPA. The donating agents and the L-DOPA hybrids reduced the release of tumor necrosis factor-\u3b1, interleukin-6 and nitric oxide from stimulated microglia, astrocytes as well as the THP-1 and U373 cell lines. They also demonstrated a neuroprotective effect by reducing the toxicity of supernatants from these stimulated cells to SH-SY5Y cells. L-DOPA itself was without effect in any of these assays. They may be useful for the treatment of PD because of their significant antiinflammatory, antioxidant and neuroprotective properties