Co-drug Research Articles

Low Dose Carbon Monoxide Is Neuroprotective in Models of Parkinson’s Disease (S42.008)

<h3>Objective:</h3> To evaluate the neuroprotective potential of low dose CO treatment in Parkinson disease (PD) models. <h3>Background:</h3> Despite the many risks of smoking tobacco, the risk of PD is markedly reduced among smokers and may derive from biological activity of specific tobacco smoke constituent(s). On the basis of accumulating evidence supporting the therapeutic potential of CO in other disease contexts, this study set out to determine whether low dose CO is neuroprotective in PD models. <h3>Design/Methods:</h3> In an AAV-alpha-synuclein (aSyn) model, rats underwent right nigral injection of AAV1/2-asynA53T and left injection of empty AAV, followed by treatment with oral CO drug product (HBI-002 10ml/kg, daily by gavage) or vehicle. In a short-term MPTP model (40mg/kg, i.p.), mice were treated with inhaled CO (iCO) (250ppm) or air. In an in vitro rotenone model, SH-SY5Y cells exposed to rotenone were treated with CO (200 ppm) or air. All analyses, including immunohistochemistry for nigral aSyn and tyrosine hydroxylase, HPLC measurement of striatal dopamine, stereological cell counting, and biochemical analyses were conducted blinded to treatment condition. <h3>Results:</h3> Each HBI-002 treatment increased carboxy-hemoglobin to 6%. In the aSyn model, treatment with HBI-002 reduced ipsilateral loss of both striatal dopamine and TH-positive neurons in the substantia nigra pars compacta, and HBI-002 reduced aSyn aggregates and aSyn S129 phosphorylation. In the MPTP model, treatment with low dose iCO also reduced loss of striatal dopamine and loss of TH+ neurons. In saline-treated mice, iCO had no effect on striatal dopamine or TH+ cell counts. HBI-002 upregulated heme oxygenase-1, HIF-1a, and cathepsin D. In the rotenone model, treatment with low dose CO reduced cell death. <h3>Conclusions:</h3> These results demonstrating reduced cell death and aSyn pathology in animal and cell models support the therapeutic potential of low dose CO for PD. <b>Disclosure:</b> Dr. Gomperts has received personal compensation in the range of $0-$499 for serving as a Consultant for EIP. Dr. Gomperts has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Jannsen. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from LBDA. The institution of Dr. Gomperts has received research support from DOD/CDMRP. The institution of Dr. Gomperts has received research support from FFFPRI. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from MJFF. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from MJFF. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from NIH. Dr. Rose has nothing to disclose. Dr. Zorlu has nothing to disclose. Dr. Xue has nothing to disclose. Dr. Cai has received personal compensation for serving as an employee of Pfizer . Ms. Lin has nothing to disclose. Mr. Lee has nothing to disclose. Dr. Gomperts has stock in Hillhurst Biopharmaceuticals inc. The institution of Dr. Gomperts has received research support from Hillhurst Biopharmaceuticals inc. Dr. Gomperts has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Schwarzschild has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bial Biotech (indirectly, as a service of the Parkinson Study Group service). The institution of Dr. Schwarzschild has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen (indirectly, as a service of the Parkinson Study Group service). The institution of Dr. Schwarzschild has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for UCB (indirectly, as a service of the Parkinson Study Group service). Dr. Schwarzschild has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eli Lilly. The institution of Dr. Schwarzschild has received research support from NIH. The institution of Dr. Schwarzschild has received research support from Parkinson’s Foundation. The institution of Dr. Schwarzschild has received research support from Michael J Fox Foundation. The institution of Dr. Schwarzschild has received research support from Farmer Family Foundation. Dr. Schwarzschild has a non-compensated relationship as a Chair, Executive Committee with the Parkinson Study Group that is relevant to AAN interests or activities. Dr. Chen has nothing to disclose.

A Theranostic Two-Tone Luminescent PhotoCORM Derived from Re(I) and (2-Pyridyl)-benzothiazole: Trackable CO Delivery to Malignant Cells.

A Re(I) carbonyl complex derived from 2-(2-pyridyl)-benzothiazole (pbt), [Re(H2O)(CO)3(pbt)](CF3SO3) (1), rapidly releases CO under low-power UV illumination. CO photorelease from 1 is accompanied by a change in luminescence from orange to deep blue. These two distinct luminescence signals have been successfully employed to track (a) the entry of the pro-drug 1 into cancer cells and (b) the end of the CO (drug) delivery step within the target.

PPKC ε mediated metalloproteinase 2 and 9 levels upon ibuprofen and lipoic acid coniugate (codrug 1) treatment in an Alzheimer disease rat brain model

Alzheimer’s Disease (AD) begins with loss of recent memory and is associated to pathological and histological hallmarks such as β amyloid plaques, neural tangles (NFT), cholinergic deficit, extensive neuronal loss and synaptic changes in the cerebral cortex and hippocampus. The amyloid cascade hypothesis implies the activity of β, γ secretases which mediate the cleavage of Amyloid Precursor Protein (APP), the formation of amyloidogenic Aβ fragment (1-42), which compacts into amyloid plaques, while the cleavage by ? secretase of APP, within the Aβ segment forms sAPP and prevents the formation of Aβ (Zetterberg et al. 2010 Exp Gerontol 45, 23-29). Among the proteases which have Aβ-degrading activity, Metalloproteinase (MMP) 2, disclosing β secretase-like activity, is included, while MMP9 seems to contribute to neuronal death (Yan et al. 2006 J Biol Chem 281, 24566-74). In addition, intracellular signalling protein Protein Kinase C (PKC) can control ? secretase, preventing the formation of β amyloid, and prolonging the life span of AD (de Barry et al. 2010 Exp Gerontol 45, 64-69). A lipophilic molecular combination (codrug 1), obtained by joining an antioxidant molecule, lipoic acid, with an anti-inflammatory compound, ibuprofen (IBU) has been synthetized in our lab and administered in a chronic treatment during intracerebroventricular infusion of Aβ (1-40) peptide in rat brains as a model of AD (Sozio et al. 2010 Arch Pharm 343,133-42). Here we show the effects exerted by codrug 1 on PKC e-mediated MMP2 and MMP9 levels regulation in Aβ (1-40) infused rat cerebral cortex. Interestingly codrug 1, lowering Metalloproteinases expression via PKC e down-modulation, seems to control Alzheimer’s disease induced cerebral amyloid deposits, neuronal death and, lastly, behavioural deterioration. Moreover the cognitive test evidences that codrug 1 treatment decreases the number of reference memory errors and the time spent to perform the test suggesting this compound as an useful therapeutical tool against AD.

Chronic Olanzapine, Serotonin Receptors, and Subsequent Serotonin Toxicity

1Rocky Mountain Poison and Drug Center, Denver, CO, and University of Colorado Denver School, of Medicine, Aurora, CO 2Rocky Mountain Poison and Drug Center, Denver, CO, University of Colorado Denver School, of Medicine, Aurora, CO and Divisions of Pharmacology, Toxicology, and Occupational and Environmental Health, University of Colorado School of Public Health, Aurora, CO [email protected]