Cyclosporine-A enhances choline acetyltransferase immunoreactivity in the septal region of adult rats.

Cyclosporine-A (CsA) is the primary anti-rejection drug used for organ and neural transplantation therapy. In addition to its immunosuppressive action, CsA has been recently shown to exert neuroprotective and neurotrophic effects in the central nervous system when able to cross the blood-brain barrier. Postulated mechanisms for these CsA-induced beneficial effects include the drug's powerful inhibition of the calcium-dependent phosphatase calcineurin (CN) and blockade of the assembly of the mitochondrial permeability transition pore. We report here, for the first time, that adult Wistar rats treated with CsA (10 mg/kg per day, i.p. for 9 days) displayed significantly reduced septal CN expression in combination with enhanced levels of septal choline acetyltransferase (ChAT) immunoreactivity as compared to controls. The observed enhancement of septal ChAT immunoreactivity suggests potential therapeutic utility of CsA for brain disorders characterized by alterations of the cholinergic system.

Cyclosporine A-induced hyperactivity in rats: is it mediated by immunosuppression, neurotrophism, or both?

Cyclosporine A (CsA) immunosuppressive treatment has become an adjunctive therapy in neural transplantation of dopamine-secreting cells for treatment of Parkinson's disease (PD). Recently, CsA and its analogues have been shown to promote trophic effects against neurodegenerative disorders, and therefore CsA may have direct beneficial effects on dopaminergic neurons and dopamine-mediated behaviors. The present study examined the interaction between the reported CsA-induced hyperactivity and the possible alterations in nigral tyrosine hydroxylase (TH)-immunoreactive neurons in rats with damaged blood-brain barrier. CsA was administered at a therapeutic dose (10 mg/kg/day, IP, for 9 days) used in neural transplantation protocol for PD animal models. CsA-treated animals displayed significantly higher general spontaneous locomotor activity than control animals at drug injection days 7 and 9. Histological assays at day 9 revealed that there was a significant increase in TH-immunoreactive neurons in the nigra of CsA-treated rats compared to that of the vehicle-treated rats. The nigral TH elevation was accompanied by suppressed calcium-phosphotase calcineurin activity, indicating an inhibition of host immune response. This is the first report of CsA exerting simultaneous immunosuppressive and neurotrophic effects, as well as increasing general spontaneous locomotor behavior. These results support the utility of CsA as a therapeutic agent for PD and other movement disorders.

Prepro-thyrotropin-releasing hormone 178-199 exerts partial protection against cerebral ischemia in adult rats.

We examined in the present study the effects of the centrally administered prepro-thyrotropin-releasing-hormone 178-199 (prepro-TRH 178-199) on cerebral ischemia induced by ligation of the middle cerebral artery (MCA) in adult Sprague-Dawley rats. Animals were intracerebrally injected with prepro-TRH 178-199 (6 microg/kg or 200 microg/kg) or saline 1-2 h before ligation of MCA. Ischemic animals that received prepro-TRH 178-199, regardless of dosage, displayed some amelioration (20%) of motor asymmetry associated with MCA ligation, while ischemic animals that received saline continued to exhibit significant asymmetrical behaviors. Interestingly, triphenyltetrazolium chloride staining (a marker for tissue metabolic activity) revealed that four of five ischemic animals that received 200 microg/kg prepro-TRH 178-199 showed a marked reduction (90-100%) in the infarction of the frontal cortex, although the posterior sections of the cortex remained infarcted. In contrast, ischemic animals that received 6 microg/kg prepro-TRH 178-199 demonstrated infarction that did not differ in size and extent from those that received saline. Post hoc examination revealed that ischemic animals treated with 200 microg/kg prepro-TRH 178-199 had significantly lower corticosterone (CORT) levels (115+/-23 ng/ml) than ischemic animals treated with 6 microg/kg prepro-TRH 178-199 or saline (288+/-51 ng/ml). The present observation provides the first evidence that prepro-TRH 178-199 can promote neuroprotection against cerebral ischemia.

CNS immunological modulation of neural graft rejection and survival.

Neural transplantation therapy as a possible alternative treatment for neurological movement disorders, such as in Parkinson's disease (PD), has accentuated research interest on the immune status of the central nervous system (CNS). Most animal studies concerned with neural transplantation for the treatment of PD have utilized dopamine (DA) neurons from tissues of the embryonic ventral mesencephalon. Rat embryonic DA neurons, grafted either as solid blocks or dissociated into a cell suspension and stereotaxically injected intraparenchymally into a rat lesion model of PD, have been shown to survive and form connections with the host brain, and ameliorate the behavioral deficits of PD. Similarly, studies on nonhuman primate models of PD provide considerable support for neural transplantation of DA neurons as an experimental clinical procedure for the treatment of PD. To this end, experimental clinical trials have been centered upon transplantation of the embryonic ventral mesencephalic cells for PD patients. Although not conclusive, the findings from clinical studies have provided some evidence that most patients with marked increases in fluorodopa uptake (indicating graft survival) have been immunosuppressed. Furthermore, immune reactions have been observed in rats xenografted with human embryonic tissue. Of note, embryonic ventral mesencephalic tissues compared to adult tissues produce better morphological and long-lasting behavioral amelioration of the neurobehavioral deficits of PD, thus advocating the use of grafts from young donors (embryo) to circumvent the CNS immune rejection. The possible graft rejection due to CNS immune reactions, coupled with the social and ethical problems surrounding the use of embryonic neural tissue, and the logistical problems concerning tissue availability have prompted the development of alternative sources of DA-secreting cells. To circumvent these obstacles, several methods have been suggested including the use of immunosuppressants such as Cyclosporine-A, transplantation of autografts, polymer-encapsulated DA-secreting cells, co-culturing and co-transplantation of DA-secreting cells with microcarrier beads, with Sertoli cells, or with fragments of a monoclonal antibody that can mask the MHC class I antigens, and genetically modifying cells that can withstand CNS immune reactions. Some of these techniques allow transplantation of allograft (same species transplantation), or even xenograft (cross species transplantation) without immunosuppression of the recipient. We discuss recent CNS immunosuppression techniques that pose some promise for enhanced survival of neural grafts. When possible, advantages and disadvantages of each method are presented. Hopefully, such critical analysis of different immunosuppression techniques will produce innovated ideas that will lead to a better understanding of CNS immune response and its modulatory function on graft rejection and survival.

Age-dependent neurobehavioral responses by young and mature adult rats to systemic kainic acid.

Neurobehavioral effects caused by the excitotoxin kainic acid (KA) have been characterized by convulsions including 'wet dog shakes' (WDS) with accompanying hippocampal degeneration in experimental animals. Accordingly, this model has been proposed for putative excitotoxin-mediated disorders, such as the temporal lobe epilepsy. There have been reports on age-dependent neurobehavioral effects of KA; however, little is known about possible correlations between neuropathology and behavioral responses to KA. The present study demonstrates that mature adult rats (12 months old) injected subcutaneously (s.c.) with KA (12 mg/kg) had severer damage to the hippocampal formation, i.e. CA3 region, compared with KA-treated young adult rats (2 months old). The mature adult animals also exhibited an earlier onset of WDS, a significantly higher number of WDS (P > 0.01), and severer convulsions compared with young adult rats. These findings indicate a positive correlation between KA-induced hippocampal damage and behavioral responses in young and mature adult rats.