Systemic lipopolysaccharide plus MPTP as a model of dopamine loss and gait instability in C57Bl/6J mice.

In most environmental models of Parkinson's disease (PD), a single neurodegenerative agent is introduced to cause nigrostriatal dopamine depletion. However, cell loss in human PD often might derive, at least in part, from multiple toxins or vulnerabilities, any one of which alone does not inevitably lead to chronic dopamine depletion. In the present research, male C57BL/6J mice were systemically administered the inflammatory bacterial endotoxin, lipopolysaccharide (LPS) and the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) alone or in combination and the behavior as well as striatal dopamine levels were compared to saline-treated mice. Mice in the combination (LPS+MPTP) group, but not in the single-factor groups, showed both dopamine depletion and parkinsonian symptoms, i.e., reduced stride length, at 4 months post-injection. MPTP alone acutely reduced striatal dopamine levels but this effect was transient as striatal dopamine recovered to normal levels after time (4 months). The LPS-only group showed no dopamine depletion or reduced stride length. These data are consistent with the view that nigrostriatal dopamine neurons might succumb after time to multiple toxic agents that independently may have only a transient, adverse effect.

Noradrenergic responses of peripheral organs to cyclophosphamide in mice.

To determine if the chemotherapeutic drug cyclophosphamide influences the activity of the sympathetic nervous system, the effects of cyclophosphamide on norepinephrine concentration in the heart, adrenal gland, spleen, and thymus gland were evaluated. Male BALB/cByJ mice were administered a single injection of cyclophosphamide (15, 50, or 100 mg/kg, i.p) or saline-vehicle. Organs were collected 72 or 120 h after injection and norepinephrine concentrations were determined by high pressure liquid chromatography with electrochemical detection. Cyclophosphamide reduced spleen, thymus gland, and heart mass while also elevating spleen and thymus gland norepinephrine concentrations (both pmoles/mg tissue and pmoles/mg protein) in a dose- and time-dependent manner. Norepinephrine concentrations in heart and adrenal gland were not altered by cyclophosphamide at any drug dose or time point. Dose- and time-dependent cyclophosphamide-mediated changes in peripheral norepinephrine levels in the spleen and thymus gland are interesting because subjects administered cyclophosphamide may be more susceptible to opportunistic infections, not only because the drug is antineoplastic, but also because the drug alters nervous system-immune system communication and the neurochemical milieu in which surviving cells interact.

Cyclophosphamide induces dose- and time-dependent elevations in spleen norepinephrine levels of BALB/c mice.

Chemotherapeutic drugs may not only kill rapidly dividing cells but may also alter the extracellular environment of surviving cells. We investigated the possibility that cyclophosphamide might alter the noradrenergic environment of the spleen. Male BALB/cByJ mice were administered a single injection of cyclophosphamide (0, 15, 50, or 100 mg/kg). Seventy-two hours after injection animals receiving 50 or 100 but not 15 mg/kg experienced elevated norepinephrine concentrations (pmol/mg) compared to animals given 0 mg/kg. The time course of changes in norepinephrine concentration was investigated 24-216 h after administration of 50 mg/kg cyclophosphamide; norepinephrine took 48 h to elevate, remained elevated for 48-96 h, and returned to vehicle-treated levels by 120 h. Cyclophosphamide in both experiments reduced spleen mass but did not alter total norepinephrine/spleen. These results suggest that low doses of cyclophosphamide can increase the norepinephrine available to influence cell-cell interactions in the spleen.