Kara B. Duffy

Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy.

Pyridoxine (vitamin B6) intoxicated rodents develop a peripheral neuropathy characterized by sensory nerve conduction deficits associated with disturbances of nerve fiber geometry and axonal atrophy. To investigate the possibility that glucagon-like peptide-1 (7-36)-amide (GLP-1) receptor agonism may influence axonal structure and function through neuroprotection neurotrophic support, effects of GLP-1 and its long acting analog, Exendin-4 (Ex4) treatment on pyridoxine-induced peripheral neuropathy were examined in rats using behavioral and morphometric techniques. GLP-1 is an endogenous insulinotropic peptide secreted from the gut in response to the presence of food. GLP-1 receptors (GLP-1R) are coupled to the cAMP second messenger pathway, and are expressed widely throughout neural tissues of humans and rodents. Recent studies have established that GLP-1 and Ex4, have multiple synergistic effects on glucose-dependent insulin secretion pathways of pancreatic beta-cells and on neural plasticity. Data reported here suggest that clinically relevant doses of GLP-1 and Ex4 may offer some protection against the sensory peripheral neuropathy induced by pyridoxine. Our findings suggest a potential role for these peptides in the treatment of neuropathies, including that associated with type II diabetes mellitus.

A blueberry-enriched diet provides cellular protection against oxidative stress and reduces a kainate-induced learning impairment in rats

Young male Fischer-344 rats were fed a diet containing 2% blueberry (BB) extract or control diet for at least 8 weeks and then received bilateral hippocampal injections of kainic acid (KA 200 ng/0.5 microl) or phosphate buffered saline (PBS). One week later rats were trained in one-way active footshock avoidance in a straight runway followed the next day by training in a footshock motivated 14-unit T-maze with documented sensitivity to hippocampal glutamatergic manipulations. Based on analyses of several performance variables, KA-treated rats exhibited clearly impaired learning performance; however, the BB diet significantly reduced this impairment. Supporting the behavioral findings, stereological assessment of CA1 pyramidal neurons documented greater neuronal loss in KA-treated controls compared to KA-treated rats on the BB diet. In an in vitro experiment, FaO cells grown in medium supplemented with serum from BB-fed rats had enhanced viability after exposure to hydrogen peroxide. These findings suggest that BB supplementation may protect against neurodegeneration and cognitive impairment mediated by excitotoxicity and oxidative stress.

Phosphodiesterase inhibition by sildenafil citrate attenuates the learning impairment induced by blockade of cholinergic muscarinic receptors in rats.

We examined whether treatment with sildenafil citrate (the active compound of Viagra), a cyclic nucleotide phosphodiesterase type 5 inhibitor (PDE5), would reverse the learning impairment induced by cholinergic muscarinic (mACh) receptor blockade [0.75 mg/kg scopolamine HCl, intraperitoneal (i.p.) injections]. Rats were pretrained in a one-way active avoidance of foot shock in a straight runway and the next day received 15 training trials in a 14-unit T-maze. Performance in this maze paradigm requires accurate responding to avoid mild foot shock and has been shown to be sensitive to aging and to impairment in central cholinergic systems. Intraperitoneal (i.p.) injections of scopolamine or saline and sildenafil or vehicle were given 30 and 15 min before training, respectively. The combined treatment conditions were as follows: saline+vehicle (control), scopolamine (0.75 mg/kg)+vehicle, and scopolamine (0.75 mg/kg)+sildenafil (1.5, 3.0, or 4.5 mg/kg). Behavioral measures of performance included deviations from the correct pathway (errors), run time from start to goal, shock frequency, and duration. Statistical analysis revealed that scopolamine impaired maze performance and that sildenafil (3.0 mg/kg) significantly attenuated this impairment in a dose-dependent manner. These results suggest that sildenafil citrate may serve as a cognitive enhancer for therapeutic treatment of cholinergic dysfunction in age-related cognitive decline and Alzheimers dementia (AD).

Phosphodiesterase inhibition facilitates cognitive restoration in rodent models of age-related memory decline.

BACKGROUND Previous studies have shown that cyclic nucleotide phosphodiesterase type 5 (PDE5) inhibition with the drugs sildenafil and vardenafil can enhance spatial performance and object recognition in rodent models of learning and memory. OBJECTIVE We review recent studies on PDE5 inhibition and report novel data that specifically tests the systemic effects of both pharmacological agents in aged rats using two different spatial learning/memory paradigms. METHODS The 14-unit T-maze was used as a test of egocentric spatial processing that requires rats to learn a series of left/right turns to avoid mild footshock. The Morris water maze is a test of allocentric spatial learning that requires the acquisition of place information to localize a hidden platform relative to distal room cues. RESULTS In both cases, acquisition (i.e., learning performance) was not improved, however after a one week drug washout period, aged animals demonstrated improved spatial memory retention compared to aged controls, ruling out simple performance effects. CONCLUSIONS These findings are discussed in relation to recent reports on the use of PDE inhibitors to treat Alzheimers disease (AD) dementia and age-related memory impairments. While some report promising pre-clinical results, others note that PDE5 may not be an appropriate target in AD due to a lack of localization within critical brain structures where therapeutic activity is needed. Despite these limitations, PDE5 inhibition may produce beneficial effects via several mechanisms that target predisposing risk factors leading to increased incidence of memory impairment in aged individuals and influence memory consolidation mechanisms that preserve long-term retention of cognitive information.

Enhancement of amphetamine-induced locomotor response in rats on different regimens of diet restriction and 2-deoxy-d-glucose treatment

Diet restriction (DR) in rodents increases lifespan, reduces age-related disease and pathology, increases stress responses, and maintains better function later into life compared with conventional ad libitum (AL) feeding. We have been investigating different DR regimens and also DR mimetics that stimulate stress response pathways that are activated by DR. By inhibiting glycolysis, feeding or injection of 2-deoxy-D-glucose (2DG) has been proposed as a DR mimetic and has been shown to provide neuroprotection. In the current study, we examined whether 2DG treatment produces behavioral changes similar to those observed in DR rats following stimulation of the dopaminergic (DA) system by D-amphetamine (AMPH). Male Fischer 344 rats were maintained on different dietary regimens: 40% daily DR (40% DR); every-other-day feeding (EOD); or AL with some groups provided food containing 0.4% 2DG or injected i.p. with 2DG. In addition, we examined the persistence of effects of DR or 2DG feeding after switching rats to AL. When locomotor activity was assessed at different time points following initiation of dietary treatments, we noted that the enhancement of AMPH-induced locomotor responses emerged earlier in DR rats than observed in 2DG fed rats, but 40% DR and EOD rats responded in a similar manner. Enhanced locomotor responses persisted in 2DG fed rats even when returned to normal diet for 1 month and in the case of DR rats even after 2 months of AL feeding. Three weeks of 2DG injections also enhanced AMPH response, but this effect was transient. The most important finding was that 2DG did not affect body weight or diet intake yet had effects similar to DR. Thus, 2DG appears to activate DA pathways in the same direction as DR does but without the necessity of reducing caloric intake.

Combined administration of subthreshold doses of the nitric oxide inhibitor, nitro-L-arginine, and muscarinic receptor antagonist, scopolamine, impairs complex maze learning in rats.

Traditionally, research into the neurobiological mechanisms of age-related memory impairments has focused on single neurotransmitter systems. As normal and abnormal age-related declines in memory function probably involve alterations in more than one system, a more effective approach for elucidating underlying neurobiological changes and resulting impairments may be to evaluate the roles of multiple systems simultaneously. This study evaluated the interaction of the cholinergic and nitric oxide systems in rats on acquisition in the 14-unit T-maze. This task requires learning a series of turns to avoid foot shock, and most likely reflects procedural learning. Administration of scopolamine (0.1 mg/kg) or Nω-nitro-L-arginine methyl ester (30 mg/kg) alone did not impair acquisition, whereas administration of the same doses in combination increased both the latency to complete the maze and number of errors committed. These data suggest that manipulation of learning and memory processes with multiple compounds potentially offers a clinically relevant paradigm for investigating cognitive function in normal and abnormal aging.