Therapeutic potential of PACAP in alcohol toxicity.

Alcohol addiction is a worldwide concern as its detrimental effects go far beyond the addicted individual and can affect the entire family as well as the community. Considerable effort is being expended in understanding the neurobiological basis of such addiction in hope of developing effective prevention and/or intervention strategies. In addition, organ damage and neurotoxicological effects of alcohol are intensely investigated. Pharmacological approaches, so far, have only provided partial success in prevention or treatment of alcohol use disorder (AUD) including the neurotoxicological consequences of heavy drinking. Pituitary adenylate cyclase-activating polypeptide (PACAP) is an endogenous 38 amino-acid neuropeptide with demonstrated protection against neuronal injury, trauma as well as various endogenous and exogenous toxic agents including alcohol. In this mini-review, following a brief presentation of alcohol addiction and its neurotoxicity, the potential of PACAP as a therapeutic intervention in toxicological consequences of this devastating disorder is discussed.

Lessons Learned from an LGBTQ Senior Center: A Bronx Tale.

This article describes an interdisciplinary pilot study exploring the impact of LGBTQ senior centers on the lives of center members. Many LGBTQ adults face the future having experienced stigma and bias, restricted rights, and rejection from family of origin, and are now growing older without the support of a partner and adult children. As a result, older LGBTQ adults experience higher rates of depression, loneliness and isolation, and shortened life expectancy as compared to non-LGBTQ peers. Findings from focus group and key informant interviews highlight features of LGBTQ senior center experiences that can significantly improve members' quality of life. These include providing family, acceptance and a home, which can have an impact on outlook and outcomes. Moreover, findings suggest the need for re-thinking hetero-normative definitions of "community" in the context of LGBTQ aging. Beyond sharing findings from the study, suggesting a conceptual framework for deepening understanding about LGBTQ aging, and identifying lines of future inquiry, the article articulates implications for social work research, practice and education. Ultimately, the article argues that social work is well positioned to improve quality of life for this under-served population when it adopts a cultural humility stance in research, practice and education.

PACAP protects against inflammatory-mediated toxicity in dopaminergic SH-SY5Y cells: implication for Parkinson's disease.

There has been a growing recognition of the role of neuroinflammation caused by microglia-exaggerated release of inflammatory mediators in the pathogenesis of Parkinson's disease (PD). Pituitary adenylate cyclase activating polypeptide (PACAP) is an endogenous 38 amino acid containing neuropeptide that has been shown to possess neurotrophic as well as neuroprotective properties. In this study, we sought to determine whether PACAP could protect SH-SY5Y dopaminergic cells against toxicity induced by inflammatory mediators. For this purpose, THP-1 cells which possess microglia-like property were stimulated by a combination of lipopolysaccharide (LPS) and interferon gamma (IFN-γ), and the media containing inflammatory mediators were isolated and applied to SH-SY5Y cells. Such treatment resulted in approximately 54 % cell death as well as a reduction in brain-derived neurotrophic factor (BDNF) and phosphorylated cyclic AMP response element-binding protein (p-CREB). Pretreatment of the SH-SY5Y cells with PACAP (1-38) dose-dependently attenuated toxicity induced by the inflammatory mediators. PACAP effects, in turn, were dose-dependently blocked by the PACAP receptor antagonist (PACAP 6-38). These results suggest protective effects of PACAP against inflammatory-induced toxicity in a cellular model of PD that is likely mediated by enhancement of cell survival markers through activation of PACAP receptors. Hence, PACAP or its agonists could be of therapeutic benefit in inflammatory-mediated PD.

Protective effects of curcumin against rotenone and salsolinol-induced toxicity: implications for Parkinson's disease.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder that results from the loss of or damage to dopaminergic cells in the substantia nigra. Exposure to either the pesticide rotenone or the endogenous neurotoxin salsolinol has been shown to mimic this dopaminergic cell loss. In this study, we first sought to determine whether combination of rotenone and salsolinol would result in an additive or synergistic toxicity. For this purpose we utilized SH-SY5Y cells, a human neuroblastoma cell line that is commonly used to model dopaminergic neurodegeneration. We then tested whether curcumin, a natural plant compound with known health benefits including potential neuroprotective properties, could also protect against rotenone and/or salsolinol-induced toxicity. Moreover, since apoptotic mechanism has been implicated in toxicity of these compounds the anti-apoptotic effect of curcumin was also evaluated. Our results indicate a synergistic toxicity of low concentrations of rotenone (1 and 5 µM) and salsolinol (25 and 50 µM) that was associated with apoptosis as determined by cell flow cytometry. There was also an increase in caspase-3 levels. Pretreatment with curcumin (1-µM) dose-dependently attenuated rotenone and/or salsolinol-induced toxicity and the associated apoptosis. These results suggest that exposure to a combination of rotenone and salsolinol may contribute to the pathology of PD, and that curcumin has a therapeutic potential in this disease.

PACAP protects against salsolinol-induced toxicity in dopaminergic SH-SY5Y cells: implication for Parkinson's disease.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an endogenous 38 amino acid containing neuropeptide with various cytoprotective functions including neuroprotection. Administration of PACAP has been shown to reduce damage induced by ischemia, trauma, or exogenous toxic substances. Moreover, mice deficient in PACAP are more vulnerable to damaging insults. In this study, we sought to determine whether PACAP may also be protective against salsolinol-induced toxicity in SH-SY5Y cells and, if so, elucidate its mechanism(s) of action. Salsolinol (SALS) is an endogenous dopamine metabolite with selective toxicity to nigral dopaminergic neurons, which are directly implicated in Parkinson's disease (PD). SH-SY5Y cells, derived from human neuroblastoma cells, express high levels of dopaminergic activity and are used extensively as a model to study these neurons. Exposure of SH-SY5Y cells to 400 µM SALS for 24 h resulted in approximately 50 % cell death that was mediated by apoptosis as determined by cell flow cytometry and increases in caspase-3 levels. Cellular toxicity was also associated with reductions in brain-derived neurotrophic factor and phosphorylated cyclic AMP response element-binding protein. Pretreatment with PACAP dose-dependently attenuated SALS-induced toxicity and the associated apoptosis and the chemical changes. PACAP receptor antagonist PACAP6-38, in turn, dose-dependently blocked the effects of PACAP. Neither PACAP nor PACAP antagonist had any effect of its own on cellular viability. These results suggest the protective effects of PACAP in a cellular model of PD. Hence, PACAP or its agonists could be of therapeutic benefit in PD.

Nicotine promotes survival of cells expressing amyloid precursor protein and presenilin: implication for Alzheimer's disease.

Amyloid-ß protein (Aß) accumulation is one of the major hallmarks of Alzheimer's disease (AD) and plays a crucial role in its pathogenesis. Cellular models whereby amyloid precursor protein (APP) is highly expressed are commonly used to test the efficacy of novel neuroprotective compounds. In addition to Aß, it is known that mutation in the protein presenilin contributes to early onset AD. Recently, a cellular neuroblastoma model where both APP and presenilin are expressed has become available. Since protective effects of nicotine against various neurotoxins have been observed, this study was designed to determine whether nicotine would also protect against cellular damage induced by APP or APP and presenilin. Wild type neuroblastoma (N2a) cell line, and those transfected with amyloid precursor protein (APP), and the combination of APP and presenilin were pretreated with various concentrations of nicotine and the survivability of the cells were determined by MTT assay. Nicotine dose dependently provided protection against cellular loss in all cell lines, with highest protection in the double transfected (44%) followed by single transfected (30%), and wild type (21%). The effects of nicotine in turn were blocked by mecamylamine, a non-selective nicotinic antagonist. These results suggest differential sensitivity of cell lines representing AD pathology to the protective effects of nicotine and provide further support of therapeutic potential of nicotinic agonists in at least a subtype of AD patients.