Methods to Investigate the Protection Against Neurodegenerative Disorders Provided by Progranulin Gene Transfer in the Brain.

Progranulin (PGRN) is a multifunctional protein that is widely expressed throughout the brain, where it has been shown to be a critical regulator of CNS inflammation (Ahmed et al., J Neuroinflammation 4:7, 2007; Yin et al., J Exp Med 207:117-128, 2010; Martens et al.

The BSSG rat model of Parkinson's disease: progressing towards a valid, predictive model of disease.

Abstract: Parkinson's disease (PD) is a neurodegenerative disorder, classically considered a movement disorder. A great deal is known about the anatomical connections and neuropathology and pharmacological changes of PD, as they relate to the loss of dopaminergic function and the appearance of cardinal motor symptoms. Our understanding of the role of dopamine in PD has led to the development of effective pharmacological treatments of the motor symptoms in the form of dopamine replacement therapy using levodopa and dopaminergic agonists.

Progranulin gene delivery reduces plaque burden and synaptic atrophy in a mouse model of Alzheimer's disease.

Progranulin (PGRN) is a multifunctional protein that is widely expressed throughout the brain, where it has been shown to act as a critical regulator of CNS inflammation and also functions as an autocrine neuronal growth factor, important for long-term neuronal survival. PGRN has been shown to activate cell signaling pathways regulating excitoxicity, oxidative stress, and synaptogenesis, as well as amyloidogenesis. Together, these critical roles in the CNS suggest that PGRN has the potential to be an important therapeutic target for the treatment of various neurodegenerative disorders, particularly Alzheimer's disease (AD).

The Progressive BSSG Rat Model of Parkinson's: Recapitulating Multiple Key Features of the Human Disease.

The development of effective neuroprotective therapies for Parkinson's disease (PD) has been severely hindered by the notable lack of an appropriate animal model for preclinical screening. Indeed, most models currently available are either acute in nature or fail to recapitulate all characteristic features of the disease. Here, we present a novel progressive model of PD, with behavioural and cellular features that closely approximate those observed in patients.

Progranulin gene delivery protects dopaminergic neurons in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by tremor, rigidity and akinesia/bradykinesia resulting from the progressive loss of nigrostriatal dopaminergic neurons. To date, only symptomatic treatment is available for PD patients, with no effective means of slowing or stopping the progression of the disease. Progranulin (PGRN) is a 593 amino acid multifunction protein that is widely distributed throughout the CNS, localized primarily in neurons and microglia.

Panax ginseng is neuroprotective in a novel progressive model of Parkinson's disease.

Panax ginseng has been used in traditional Chinese medicine for centuries. Among its various benefits is a pluripotent targeting of the various events involved in neuronal cell death. This includes anti-inflammatory, anti-oxidant, and anti-apoptotic effects.

Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease.

Leucine-rich repeat kinase-2 (LRRK2) mutations are a common cause of Parkinson's disease. Here we identify inhibitors of LRRK2 kinase that are protective in in vitro and in vivo models of LRRK2-induced neurodegeneration. These results establish that LRRK2-induced degeneration of neurons in vivo is kinase dependent and that LRRK2 kinase inhibition provides a potential new neuroprotective paradigm for the treatment of Parkinson's disease.

Agonist-induced restoration of hippocampal neurogenesis and cognitive improvement in a model of cholinergic denervation.

Loss of basal forebrain cholinergic innervation of the hippocampus and severe neuronal loss within the hippocampal CA1 region are early hallmarks of Alzheimer's disease, and are strongly correlated with cognitive status. Various therapeutic approaches involve attempts to enhance neurotransmission or to provide some level of neuroprotection for remaining cells. An alternative approach may involve the generation of new cells to replace those lost in AD.

Food restriction enhances peak corticosterone levels, cocaine-induced locomotor activity, and DeltaFosB expression in the nucleus accumbens of the rat.

Chronic stress has been known to potentiate addictive behaviours in both human addicts and experimental animals. In the present study, chronic mild food restriction was used as a stressor to investigate its effect on the locomotor simulant effects of cocaine as well as FosB expression in the nucleus accumbens and caudate putamen. Chronic mild food restriction enhanced the locomotor response to the first cocaine injection, such that chronically food restricted animals showed a significant increase in activity upon an initial administration of 15 mg/kg of cocaine, an effect which only became apparent in control animals after repeated injections.

Dopamine D3 receptor agonist delivery to a model of Parkinson's disease restores the nigrostriatal pathway and improves locomotor behavior.

The presence of endogenous stem cell populations in the adult mammalian CNS suggests an innate potential for regeneration and represents a potential resource for neuroregenerative therapy aimed at the treatment of neurodegenerative disorders, such as Parkinson's disease. However, it is first necessary to examine the microenvironmental signals required to activate these innate reparative mechanisms. The small molecule neurotransmitter dopamine has been shown to regulate cell cycle in developing and adult brain, and the D3 receptor is known to play an important role in dopaminergic development.

Induction of neurogenesis in the adult rat subventricular zone and neostriatum following dopamine D3 receptor stimulation.

Discrete regions of the adult CNS, including the subventricular zone (SVZ), do retain the capacity for neurogenesis. These progenitor cells may represent a potential new source of cells for replacement therapies in neuroregenerative diseases. An understanding of the microenvironmental signals regulating neurogenesis in the adult brain would facilitate the development of such therapeutic approaches.

Neuroprotective actions of the ginseng extract G115 in two rodent models of Parkinson's disease.

The herbal remedy, ginseng, has recently been demonstrated to possess neurotrophic and neuroprotective properties, which may be useful in preventing various forms of neuronal cell loss including the nigrostriatal degeneration seen in Parkinson's disease (PD). In these studies, we examine the potential neuroprotective actions of the ginseng extract, G115, in two rodent models of PD. Animals received oral administration of G115 prior to and/or following exposure to the parkinsonism-inducing neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), in mice, or its toxic metabolite, 1-methyl-4-phenylpyridinium (MPP(+)), in rats.