Effects of sildenafil on nigrostriatal dopamine neurons in a murine model of Parkinson's disease.

The objective of this study was to determine if the phosphodiesterase 5 (PDE-5) inhibitor, sildenafil, could be used as a neuroprotective agent in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson's disease. The underlying hypothesis of these studies is that blockade of PDE-5 catabolism of cGMP will attenuate the loss of nigrostriatal dopamine (NSDA) neurons following chronic neurotoxin exposure. Chronic MPTP-treated mice were administered sildenafil using three different regimens. Animals were: 1) treated with sildenafil and then exposed to chronic MPTP; 2) treated concurrently with sildenafil and MPTP; and 3) first exposed to MPTP and subsequently treated with sildenafil. End points of neurotoxicity included dopamine (DA) and tyrosine hydroxylase (TH) concentrations in NSDA axon terminals in the striatum, and stereological cell counts of TH immunoreactive neurons in the substantia nigra. Results reveal that sildenafil did not prevent neurotoxicity produced by chronic MPTP exposure regardless of the treatment paradigms employed. On the other hand, sildenafil did not produce any deleterious effect on NSDA neuron function nor did it potentiate the neurotoxic effects of MPTP. These results suggest that sildenafil would not accelerate DA cell loss when used as a treatment for erectile dysfunction in men diagnosed with Parkinson's disease.

Lack of D2 receptor mediated regulation of dopamine synthesis in A11 diencephalospinal neurons in male and female mice.

Dopamine (DA) neurons comprising the A11 diencephalospinal system represent the major source of DA innervation to the spinal cord. These neurons project axons throughout the rostrocaudal extent of the spinal cord, terminating predominantly in the dorsal horn. Loss of DA-mediated sensorimotor function in the lumbar segment of spinal cord is implicated in the etiology of Restless Legs Syndrome (RLS), which is more prevalent in females as compared with males. The purpose of the present study was to compare the density (DA concentrations) and catabolic activity (3,4-dihydroxyphenylacetic acid; DOPAC) of A11 DA neurons innervating the lumbar spinal cord of male and female C57/BL6 mice, and to determine if there is a sexual difference in the regulation of these neurons by D2 autoreceptor-mediated mechanisms. DA concentrations in the lumbar spinal cord were higher in males, suggesting a greater A11 DA innervation as compared with females, whereas there was no sexual difference in the activity (DOPAC/DA ratio) of these DA neurons under basal conditions. Blockade of D2 receptors with raclopride caused a significant increase in the DOPAC/DA ratio in the striatum and nucleus accumbens in both males and females, but had no effect in the spinal cord. Blockade of neuronal impulse flow and DA release with gamma-butyrolactone (GBL) increased DA concentrations in the spinal cord, but this increase was not prevented by pretreatment with the D2 agonist quinelorane. These results are consistent with the conclusion that A11 diencephalospinal DA neurons in both males and females lack presynaptic synthesis modulating D2 autoreceptors.

Comparison of the D2 receptor regulation and neurotoxicant susceptibility of nigrostriatal dopamine neurons in wild-type and CB1/CB2 receptor knockout mice.

Motor dysfunctions of Parkinson Disease (PD) are due to the progressive loss of midbrain nigrostriatal dopamine (NSDA) neurons. Evidence suggests a role for cannabinoid receptors in the neurodegeneration of these neurons following neurotoxicant-induced injury. This work evaluates NSDA neurons in CB1/CB2 knockout (KO) mice and tests the hypothesis that CB1/CB2 KO mice are more susceptible to neurotoxicant exposure. NSDA neuronal indices were assessed using unbiased stereological cell counting, high pressure liquid chromatography coupled with electrochemical detection or mass spectrometry, and Western blot. Results reveal that CB1 and CB2 cannabinoid receptor signaling is not necessary for the maintenance of a normally functioning NSDA neuronal system. Mice lacking CB1 and CB2 receptors were found to be equally susceptible to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP). These studies support the use of CB1/CB2 KO mice for investigating the cannabinoid receptor-mediated regulation of the NSDA neuronal system in models of PD.