Biomedical subjects

Michael I Sandstrom

Publications and source records attributed to Michael I Sandstrom.

4 recordsLinked to original sources

PubMed2006

Neurotrophic enhancers as therapy for behavioral deficits in rodent models of Huntington's disease: use of gangliosides, substituted pyrimidines, and mesenchymal stem cells.

The interest in using neurotrophic factors as potential treatments for neurodegenerative disorders, such as Huntington's disease, has grown in the past decade. A major impediment for the clinical utility of neurotrophic factors is their inability to cross the blood-brain barrier in therapeutically significant amounts. Although several novel mechanisms for delivering exogenous neurotrophins to the brain have been developed, most of them involve invasive procedures or present significant risks. One approach to circumventing these problems is using therapeutic agents that can be administered systemically and have the ability to enhance the activity of neurotrophic factors. This review highlights the use of gangliosides, substituted pyrimidines, and mesenchymal stem cells as neurotrophic enhancers that have significant therapeutic potential while avoiding the pitfalls of delivering exogenous neurotrophic factors through the blood-brain barrier. The review focuses on the potential of these neurotrophic enhancers for treating the behavioral deficits in rodent models of Huntington's disease.

Animals↗

PubMed2005

Extracellular ascorbate modulates cortically evoked glutamate dynamics in rat striatum.

To determine if extracellular ascorbate, which may increase by several hundred micromolar in striatum during behavioral activation, directly alters glutamate transmission, we monitored striatal glutamate transients evoked by electrical stimulation of cerebral cortex in anesthetized rats tested with varying concentrations of ascorbate (0, 50, 200, and 500 microM) by reverse dialysis. Capillary electrophoresis coupled with laser-induced fluorescence detection was used to analyze dialysates collected at 3-s intervals. Ascorbate elevated striatal glutamate in a concentration-dependent fashion. Addition of 500 microM ascorbate not only more than doubled basal glutamate levels relative to the ascorbate-free condition, but significantly increased both the magnitude of the electrically evoked glutamate response as well as its subsequent return to baseline. In fact, the time required to return to within 10% of the pre-stimulation baseline increased by >100s. Reverse dialysis of iso-ascorbate, in contrast, had no effect on stimulation-evoked glutamate release arguing against an antioxidant effect. It appears, therefore, that the level of extracellular ascorbate plays a critical role in regulating corticostriatal glutamate transmission.

Animals↗

PubMed2003

Neurochemical correlates of sparing from motor deficits in rats depleted of striatal dopamine as weanlings.

The behavioral and neurochemical effects of striatal DA depletions were investigated in rats lesioned as weanlings (Day 27) or as adults (250-300 g). Administration of 6-OHDA into the medial forebrain bundle resulted in comparably large (> or = 95%) depletions of tissue levels of DA in both age groups. As expected, rats depleted of DA as adults exhibited marked deficits in motoric behavior and body weight regulation that persisted for the 8 days of postsurgical observation. In contrast, rats depleted of DA as weanlings were spared from such deficits, and their behavior closely resembled that of age-matched controls. Microdialysis studies revealed dialysate levels of striatal DA that paralleled these age-dependent behavioral differences. At a time when age-related behavioral differences were still quite pronounced (5-6 days postsurgery), basal DA levels were reduced by 80% of control values in rats lesioned as adults whereas basal DA levels in rats lesioned as weanlings were unchanged relative to their controls. Finally, adults depleted of striatal DA as weanlings were no more sensitive to the movement-impairing effects of intrastriatal sulpiride (3.0 or 10.0 micrograms/hemisphere) infusions than were control rats. These data suggest that weanlings compensate for large, but incomplete, denervation of striatal DA with markedly enhanced release and turnover from residual terminals. This developmental plasticity may prevent the occurrence of behavioral deficits soon after the lesion and also the supersensitivity to the challenging effects of DA antagonists as animals grow into adulthood.

Age Factors↗

PubMed2003

Characterization of striatal activity in conscious rats: contribution of NMDA and AMPA/kainate receptors to both spontaneous and glutamate-driven firing.

Single-unit activity in the striatum of unrestrained, conscious rats was characterized by extracellular recording in combination with iontophoresis. To avoid the confounding effect of motor-related changes in firing rate, measurements were restricted to periods when animals were at quiet rest. Recording electrodes were lowered stepwise through 4.0 mm of anterior striatum in 36 equal ventral movements of 111 microm to assess the ratio of spontaneously active vs. silent neurons. Spontaneous activity was assessed at each step followed by iontophoretic glutamate (GLU) application to expose silent neurons. Eleven such experimental sessions resulted in a total of 100 spontaneously active and 264 silent neurons, indicating that without overt movement the large majority (72.7%) of striatal cells are silent. Spontaneously active neurons, moreover, discharged at low rates (4.85 +/- 0.85 spikes/s). In separate experiments, both the AMPA/kainate (CNQX: 6-cyano-2,3-dihydroxy-7-nitro-quinoxaline disodium salt) and NMDA (AP5: D-(-)-2-amino-5-phosphonovaleric acid) GLU-receptor antagonists blocked the activity of most spontaneously active (83% CNQX, 69% AP5), and GLU-stimulated silent (68% CNQX, 98% AP5) units. Collectively, our results are consistent with an overall low level of striatal activity in the absence of strong excitatory input. When neuronal activity is initiated, however, it appears that both NMDA and AMPA/kainate receptors are critical for maintaining continuous impulse activity.

2-Amino-5-phosphonovalerate↗