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The effects of previous chronic immobilization stress on the physiological responses of male rats to a novel chronic stressor (shock) were studied. Previous chronic exposure to immobilization reduced adrenocorticotropin (ACTH) and lactate responses to acute immobilization stress without altering the response to a novel acute stressor (tail shock). When subjected to chronic tail shock, body weight inhibition caused by chronic shock was greater in the rats not previously exposed to chronic immobilization, which suggests that there is cross-adaptation between different stressors. However, adrenocorticotropin adaptation to chronic shock was impaired by previous chronic immobilization. These data indicate that the existence of cross-adaptation to stressors might depend on the variable measured, the central nervous system pathways controlling the pituitary-adrenal axis being, apparently, resistant to cross-adaptation. This lack of cross-adaptation at certain levels can assure the maintenance of an adequate response to unknown environmental stimuli.

Cyclic GMP (cGMP)-mediated pathways regulate inflammatory responses in immune and CNS cells. Recently, cGMP phosphodiesterase inhibitors such as sildenafil, commonly used to treat sexual dysfunction in humans including multiple sclerosis (MS) patients, have been reported to be neuroprotective in animal models of stroke, Alzheimer's disease, and focal brain lesion. In this work, we have examined if sildenafil ameliorates myelin oligodendrocyte glycoprotein peptide (MOG₃₅₋₅₅)-induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We show for the first time that treatment with sildenafil after disease onset markedly reduces the clinical signs of EAE by preventing axonal loss and promoting remyelination. Furthermore, sildenafil decreases CD3+ leukocyte infiltration and microglial/macrophage activation in the spinal cord, while increasing forkhead box transcription factor 3-expressing T regulatory cells (Foxp3 Tregs). However, sildenafil treatment did not significantly affect MOG₃₅₋₅₅-stimulated proliferation or release of Th1/Th2 cytokines in splenocytes but decreased ICAM-1 in spinal cord infiltrated cells. The presence of reactive astrocytes forming scar-like structures around infiltrates was enhanced by sildenafil suggesting a possible mechanism for restriction of leukocyte spread into healthy parenchyma. These results highlight novel actions of sildenafil that may contribute to its beneficial effects in EAE and suggest that treatment with this widely used and well-tolerated drug may be a useful therapeutic intervention to ameliorate MS neuropathology.

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