Long-term effects of LPS and high-fat diet on dopaminergic neurodegeneration

Mounting evidence suggests that inflammation is involved in the etiology of neurodegenerative disorders such as Parkinson's disease. It has been reported that the long-term effect of five doses of lipopolysaccharide from Gram-negative bacteria in mice caused activation of microglia and dopaminergic neurodegeneration that was reflected as decreased locomotor activity. In the current study, it is hypothesized that IL-1 beta, a potent proinflammatory cytokine synthesized and released by glia cells, could be mediating the LPS-induced dopaminergic neurodegeneration and that the chronic low-grade inflammatory state caused by diet-induced obesity would exacerbate LPS-induced neurodegeneration. To ascertain the participation of IL-1 beta, three strains of mice were employed: a control [wild type (WT)], a strain lacking the endogenous antagonist of IL-1, namely IL-1 receptor antagonist (IL-1ra-/-), and a mouse strain deficient in caspase-1 (Casp-1-/-), a protease that cleaves the immature IL-1 beta into the mature, biologically active form. Mice of the three genotypes were fed a regular diet (RD) and additionally WT mice were fed a high-fat diet (HFD). All mouse groups were challenged with intraperitoneal injections of either saline or LPS (5 mg/kg; one or five times on a monthly basis). Significant genotype and diet effects were observed in behavioral, metabolic and inflammatory outcomes over a period of 9 to 15 months, whereas the effect of LPS was modest or undetectable. Compared to WT mice, Casp-1-/- mice preserved their locomotor activities, while IL-1ra-/- mice showed a time-dependent decline in motor and coordinative abilities. Non-motor symptoms included age-related development of anxiety-like behavior in IL-1ra-/- mice. Impairment of cognitive function was observed in Casp-1-/- mice. Since insulin and leptin may modulate dopamine neurotransmission, plasma levels of these two hormones were assessed. Casp-1-/- mice had increased plasma insulin levels but were not glucose intolerant, whereas IL-1ra-/- mice were hypoinsulinemic, but insulin sensitive. Leptin levels were reduced in both genotypes (Casp-1-/- and IL-1ra-/-). Casp-1-/- mice had intact dopamine neurons and less activated microglia cells. Dopamine neurodegeneration was observed in IL-1ra-/- mice and accompanied by higher, but non-significant activation of microglia. The connection between peripheral and central inflammation was assessed by plasma level of monocyte chemoattractant protein-1 (MCP-1). Plasma MCP-1 tended to be increased by repeated LPS injections in WT mice and surprisingly it was reduced by single and repeated LPS injections in both Casp-1-/- and IL-1ra-/- mice. Significant differences in final outcomes were observed between the two diet-fed groups of mice. LPS treatments did not induce motor decline in RD and HFD-fed mice during nine months of experiments. However, HFD mice showed symptoms of akinesia, bradykinesia, dyskinesia and reduced coordinative abilities. Non-motor symptoms observed in HFD mice were anxiety-like behavior in novelty suppressed feeding test, cognitive and partial memory impairment. HFD mice displayed glucose intolerance, high levels of leptin and insulin. Dopamine neurons were not affected by HFD and significant decreases were induced by repeated LPS injections. Loss of neurons was not accompanied with increased activation of microglia cells and MCP-1. Overall, the data shown here emphasized the importance of the IL-1 signaling pathway in dopaminergic neurodegeneration

Partial inhibition of mitochondrial complex I ameliorates Alzheimer\u27s disease pathology and cognition in APP/PS1 female mice.

Alzheimer\u27s Disease (AD) is a devastating neurodegenerative disorder without a cure. Here we show that mitochondrial respiratory chain complex I is an important small molecule druggable target in AD. Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 female mice, a translational model of AD. Treatment of symptomatic APP/PS1 mice with complex I inhibitor improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET, 31P NMR, and metabolomics. Cross-validation of the mouse and the human transcriptomic data from the NIH Accelerating Medicines Partnership-AD database demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients

Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement

Interleukin-1 (IL-1), a proinflammatory cytokine synthesized and released by activated microglia, can cause dopaminergic neurodegeneration leading to Parkinsons disease (PD). However, it is uncertain whether IL-1 can act directly, or by exacerbating the harmful actions of other brain insults. To ascertain the role of the IL-1 pathway on dopaminergic neurodegeneration and motor skills during aging, we compared mice with impaired [caspase-1 knockout (casp1(-/-))] or overactivated IL-1 activity [IL-1 receptor antagonist knockout (IL-1ra(-/-))] to wild-type (wt) mice at young and middle age. Their motor skills were evaluated by the open-field and rotarod tests, and quantification of their dopamine neurons and activated microglia within the substantia nigra were performed by immunohistochemistry. IL-1ra(-/-) mice showed an age-related decline in motor skills, a reduced number of dopamine neurons, and an increase in activated microglia when compared to wt or casp1(-/-) mice. Casp1(-/-) mice had similar changes in motor skills and dopamine neurons, but fewer activated microglia cells than wt mice. Our results suggest that the overactivated IL-1 pathway occurring in IL-1ra(-/-) mice in the absence of inflammatory interventions (e.g., intracerebral injections performed in animal models of PD) increased activated microglia, decreased the number of dopaminergic neurons, and reduced their motor skills. Decreased IL-1 activity in casp1(-/-) mice did not yield clear protective effects when compared with wt mice. In summary, in the absence of overt brain insults, chronic activation of the IL-1 pathway may promote pathological aspects of PD per se, but its impairment does not appear to yield advantages over wt mice.Funding Agencies|John Curtin School of Medical Research, The Australian National University</p

Alterations of Amphetamine Reward by Prior Nicotine and Alcohol Treatment: The Role of Age and Dopamine.

Evidence suggests that nicotine and alcohol can each serve as a gateway drug. We determined whether prior nicotine and alcohol treatment would alter amphetamine reward. Also, we examined whether age and dopaminergic neurotransmission are important in this regard. Male and female adolescent and adult C57BL/6J mice were tested for baseline place preference. Mice then received six conditioning with saline/nicotine (0.25 mg/kg) twice daily, followed by six conditioning with saline/ethanol (2 g/kg). Control mice were conditioned with saline/saline throughout. Finally, mice were conditioned with amphetamine (3 mg/kg), once in the nicotine-alcohol-paired chamber, and tested for place preference 24 h later. The following day, mice were challenged with amphetamine (1 mg/kg) and tested for place preference under a drugged state. Mice were then immediately euthanized, their brain removed, and nucleus accumbens isolated and processed for the level of dopamine receptors and transporter and glutamate receptors. We observed a greater amphetamine-induced place preference in naïve adolescents than adult mice with no change in state-dependent place preference between the two age groups. In contrast, amphetamine induced a significant place preference in adult but not adolescent mice with prior nicotine-alcohol exposure under the drug-free state. The preference was significantly greater in adults than adolescents under the drugged state. The enhanced response was associated with higher dopamine-transporter and D1 but reduced D2 receptors' expression in adult rather than adolescent mice, with no changes in glutamate receptors levels. These results suggest that prior nicotine and alcohol treatment differentially alters amphetamine reward in adult and adolescent mice. Alterations in dopaminergic neurotransmission may be involved in this phenotype

Effects of nicotine on homeostatic and hedonic components of food intake.

Chronic tobacco use leads to nicotine addiction that is characterized by exaggerated urges to use the drug despite the accompanying negative health and socioeconomic burdens. Interestingly, nicotine users are found to be leaner than the general population. Review of the existing literature revealed that nicotine affects energy homeostasis and food consumption via altering the activity of neurons containing orexigenic and anorexigenic peptides in the brain. Hypothalamus is one of the critical brain areas that regulates energy balance via the action of these neuropeptides. The equilibrium between these two groups of peptides can be shifted by nicotine leading to decreased food intake and weight loss. The aim of this article is to review the existing literature on the effect of nicotine on food intake and energy homeostasis and report on the changes that nicotine brings about in the level of these peptides and their receptors that may explain changes in food intake and body weight induced by nicotine. Furthermore, we review the effect of nicotine on the hedonic aspect of food intake. Finally, we discuss the involvement of different subtypes of nicotinic acetylcholine receptors in the regulatory action of nicotine on food intake and energy homeostasis

Effects of nicotine on homeostatic and hedonic components of food intake.

Chronic tobacco use leads to nicotine addiction that is characterized by exaggerated urges to use the drug despite the accompanying negative health and socioeconomic burdens. Interestingly, nicotine users are found to be leaner than the general population. Review of the existing literature revealed that nicotine affects energy homeostasis and food consumption via altering the activity of neurons containing orexigenic and anorexigenic peptides in the brain. Hypothalamus is one of the critical brain areas that regulates energy balance via the action of these neuropeptides. The equilibrium between these two groups of peptides can be shifted by nicotine leading to decreased food intake and weight loss. The aim of this article is to review the existing literature on the effect of nicotine on food intake and energy homeostasis and report on the changes that nicotine brings about in the level of these peptides and their receptors that may explain changes in food intake and body weight induced by nicotine. Furthermore, we review the effect of nicotine on the hedonic aspect of food intake. Finally, we discuss the involvement of different subtypes of nicotinic acetylcholine receptors in the regulatory action of nicotine on food intake and energy homeostasis

The role of pituitary adenylyl cyclase-activating polypeptide in the motivational effects of addictive drugs.

Pituitary adenylyl cyclase activating polypeptide (PACAP) was originally isolated from the hypothalamus and found to stimulate adenylyl cyclase in the pituitary. Later studies showed that this peptide and its receptors (PAC1, VPAC1, and VPAC2) are widely expressed in the central nervous system (CNS). Consistent with its distribution in the CNS, the PACAP/PAC1 receptor system is involved in several physiological responses, such as mediation of the stress response, modulation of nociception, regulation of prolactin release, food intake, etc. This system is also implicated in different pathological states, e.g., affective component of nociceptive processing, anxiety, depression, schizophrenia, and post-traumatic stress disorders. A review of the literature on PubMed revealed that PACAP and its receptors also play a significant role in the actions of addictive drugs. The goal of this review is to discuss the literature regarding the involvements of PACAP and its receptors in the motivational effects of addictive drugs. We particularly focus on the role of this peptide in the motivational effects of morphine, alcohol, nicotine, amphetamine, methamphetamine, and cocaine. This article is part of the special issue on Neuropeptides