Neuroprotective and neuroregenerative effects of trophic factors

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1. BMP7: In primary dopaminergic neuronal culture, BMP7 reduced MA mediated toxicity (i.e. decreased TH immunoreactivity and increasing TUNEL labeling). BMP7 also reduced MA mediated toxicity in vivo. Intra-cerebroventricular administration of BMP7 antagonized MA-induced changes in TH immunoreactivity in striatum and locomotor activity in mice. We found that intracerebroventricular administration of 9-cis-retinoic acid (9cRA) enhanced BMP7 mRNA expression, detected by RTPCR. Pretreatment with 9cRA attenuated the loss of TH immunoreactivity in striatum after high dose of MA administration. In stroke rats, pretreatment with 9cRA increased locomotor activity and attenuated neurological deficits 2 days after stroke. 9cRA also reduced cerebral infarction and TUNEL labeling. These protective responses were antagonized by BMP antagonist noggin given at one day after 9cRA injection. Taken together, our data suggest that 9cRA has protective effects and these effects involve BMPs. 2. MANF: We first examined the interaction of MANF and methamphetamine (MA) in primary ventral mesencephalic cultures containing dopaminergic neurons. Our preliminary data indicate that MANF attenuated MA toxicity in dopaminergic neurons in culture. We also found that MANF reduced ischemic brain injury and promoted behavioral recovery. Pre-stroke delivery of MANF protein, at a dose of 6 g, reduced cerebral infarction, suppressed DNA fragmentation, and facilitated motor recovery in stroke rats. Local administration of AAV-MANF enhanced MANF expression in neurons and glia in cerebral cortex. Pretreatment with AAV-MANF reduced the volume of cerebral infarction and facilitated behavioral recovery in stroke rats. Our data suggest that administration of either MANF protein or AAV-MANF reduces ischemic brain injury. 3. CDNF: We examined whether CDNF injections into striatum of C57/Bl6 mice have neuroprotective and neurorestorative properties for the nigrostriatal dopamine system after MPTP injections. We found that bilateral striatal CDNF injections, given 20-h before MPTP exposure, improved horizontal and vertical motor behavior when measured 2 weeks afterwards. In addition, CDNF pre-treatment increased tyrosine hydroxylase (TH)-immunoreactivity in the striatum and in the substantia nigra pars reticulata (SNpr), as well as number of TH-positive cells in substantia nigra pars compacta (SNpc). Post-treatment with CDNF, given 1 week after MPTP injections, increased horizontal and vertical behavior of mice. Furthermore, dopamine fiber densities in striatum and the number of TH positive cells in SNpc were increased after CDNF injections. We conclude that intrastriatal CDNF administration is both neuroprotective and neurorestorative for the nigrostriatal dopamine system in the MPTP model, which supports the development of CDNF-based treatment strategies for Parkinsons disease. 4. Nurr1: We found that METH binge exposure in adolescence led to greater damage in the nigrostrial dopaminergic system when mice were exposed to METH binge later in life, suggesting a long-term adverse effect on the dopaminergic system. Compared to naive mice that received METH binge treatment for the first time, mice pretreated with METH in adolescence showed a greater loss of tyrosine hydroxylase (TH) immunoreactivity in striatum, loss of THir fibers in the substantia nigra reticulata (SNr) as well as decreased dopamine transporter (DAT) level and compromised DA clearance in striatum. These effects were further exacerbated in Nurr1 heterozygous mice. Our data suggest that a prolonged adverse effect exists following adolescent METH binge exposure which may lead to greater damage to the dopaminergic system when exposed to repeated METH later in life. Furthermore, our data support that Nurr1 mutations or deficiency could be a potential genetic predisposition which may lead to higher vulnerability in some individuals.