Delayed caffeine treatment prevents nigral dopamine neuron loss in a progressive rat model of Parkinson's disease

Department of Neurology, UMDNJ Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Experimental Neurology (Impact Factor: 4.7). 01/2012; 234(2):482-7. DOI: 10.1016/j.expneurol.2012.01.022
Source: PubMed


Parkinson's disease (PD) is characterized by a prominent degeneration of nigrostriatal dopamine (DA) neurons with an accompanying neuroinflammation. Despite clinical and preclinical studies of neuroprotective strategies for PD, there is no effective treatment for preventing or slowing the progression of neurodegeneration. The inverse correlation between caffeine consumption and risk of PD suggests that caffeine may exert neuroprotection. Whether caffeine is neuroprotective in a chronic progressive model of PD has not been evaluated nor is it known if delayed caffeine treatment can stop DA neuronal loss. We show that a chronic unilateral intra-cerebroventricular infusion of 1-methyl-4-phenylpyridinium in the rat brain for 28 days produces a progressive loss of DA and tyrosine hydroxylase in the ipsilateral striatum and a loss of DA cell bodies and microglial activation in the ipsilateral substantia nigra. Chronic caffeine consumption prevented the degeneration of DA cell bodies in the substantia nigra. Importantly, neuroprotection was still apparent when caffeine was introduced after the onset of the neurodegenerative process. These results add to the clinical relevance for adenosine receptors as a disease-modifying drug target for PD.

Download full-text


Available from: Jason R Richardson
  • Source
    • "Galantamine is used to treat patients with Alzheimer's disease (Houghton and Howes, 2005). The psychoactive effects of caffeine are well known, and recent findings further suggest that caffeine consumption can enhance synaptic plasticity/learning and memory, and may help forestall neurodegeneration in Alzheimer's and Parkinson's diseases (Laurent et al., 2014; Sallaberry et al., 2013; Sonsalla et al., 2012). Psilocybin is an alkaloid present in numerous species of mushroom in the genus Psilocybe, and is widely known as a potent hallucinogen that acts as a partial agonist of serotonin receptors. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The impact of dietary factors on brain health and vulnerability to disease is increasingly appreciated. The results of epidemiological studies, and intervention trials in animal models suggest that diets rich in phytochemicals can enhance neuroplasticity and resistance to neurodegeneration. Here we describe how interactions of plants and animals during their co-evolution, and resulting reciprocal adaptations, have shaped the remarkable characteristics of phytochemicals and their effects on the physiology of animal cells in general, and neurons in particular. Survival advantages were conferred upon plants capable of producing noxious bitter-tasting chemicals, and on animals able to tolerate the phytochemicals and consume the plants as an energy source. The remarkably diverse array of phytochemicals present in modern fruits, vegetables spices, tea and coffee may have arisen, in part, from the acquisition of adaptive cellular stress responses and detoxification enzymes in animals that enabled them to consume plants containing potentially toxic chemicals. Interestingly, some of the same adaptive stress response mechanisms that protect neurons against noxious phytochemicals are also activated by dietary energy restriction and vigorous physical exertion, two environmental challenges that shaped brain evolution. In this perspective article, we describe some of the signaling pathways relevant to cellular energy metabolism that are modulated by 'neurohormetic phytochemicals' (potentially toxic chemicals produced by plants that have beneficial effects on animals when consumed in moderate amounts). We highlight the cellular bioenergetics-related sirtuin, adenosine monophosphate activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and insulin-like growth factor 1 (IGF-1) pathways. The inclusion of dietary neurohormetic phytochemicals in an overall program for brain health that also includes exercise and energy restriction may find applications in the prevention and treatment of a range of neurological disorders. Published by Elsevier Ltd.
    Full-text · Article · Apr 2015 · Neurochemistry International
  • Source
    • "Decreased activity in the basal ganglia is thought to underlie some of the primary symptoms (tremor, bradykinesia) that are observed in Parkinson’s disease. Experimentally, a number of studies have shown that adenosine receptor antagonists can reduce tremor, improve motor output and may even be neuroprotective [78]–[80], and for this reason these receptors have been targets for the treatment of parkinsonism. It is interesting that in this study, the mouse strains that had lower levels of ADO are those that are generally more sensitive to xenobiotic agents used in modeling of Parkinson’s disease, including MPTP and paraquat [81]–[84]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adenosine (ADO), a non-classical neurotransmitter and neuromodulator, and its metabolites adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP), have been shown to play an important role in a number of biochemical processes. Although their signaling is well described, it has been difficult to directly, accurately and simultaneously quantitate these purines in tissue or fluids. Here, we describe a novel method for measuring adenosine (ADO) and its metabolites using high performance liquid chromatography with electrochemical detection (HPLC-ECD). Using this chromatographic technique, we examined baseline levels of ADO and ATP, ADP and AMP in 6 different brain regions of the C57BL/6J mouse: stratum, cortex, hippocampus, olfactory bulb, substantia nigra and cerebellum and compared ADO levels in 5 different strains of mice (C57BL/6J, Swiss-Webster, FVB/NJ, 129P/J, and BALB/c). These studies demonstrate that baseline levels of purines vary significantly among the brain regions as well as between different mouse strains. These dissimilarities in purine concentrations may explain the variable phenotypes among background strains described in neurological disease models.
    Full-text · Article · Mar 2014 · PLoS ONE
  • Source
    • "It is important to note that a caffeine tolerance does not develop with long-term exposure in mice (Xu et al., 2002) and neuroprotection is still apparent with caffeine intake after the onset of neurodegeneration in rats (Sonsalla et al., 2012). Genetic and pharmacological data from rodent studies indicate that caffeine reduces dopaminergic toxicity and slows disease progression through antagonism of adenosine A 2A receptors (Morelli et al., 2010; Prediger, 2010; Xiao et al., 2011; Sonsalla et al., 2012). Inhibition of glutamate neurotransmission using A 2A receptor antagonists, may relieve motor symptoms and provide neuroprotection in models of late-stage PD (reviewed in Popoli et al., 2004; Chen et al., 2007b). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease (PD) is the second most prevalent neurodegenerative disease in ageing individuals. It is now clear that genetic susceptibility and environmental factors play a role in disease etiology and progression. Because environmental factors are involved with the majority of the cases of PD, it is important to understand the role nutrition plays in both neuroprotection and neurodegeneration. Recent epidemiological studies have revealed the promise of some nutrients in reducing the risk of PD. In contrast, other nutrients may be involved with the etiology of neurodegeneration or exacerbate disease progression. This review summarizes the studies that have addressed these issues and describes in detail the nutrients and their putative mechanisms of action in PD.
    Full-text · Article · Mar 2014 · Frontiers in Aging Neuroscience
Show more