Optimal effectiveness of BDNF for fetal nigral transplants coincides with the ontogenic appearance of BDNF in the striatum.

Transplantation of fetal nigral dopamine neurons into the caudate and putamen of Parkinson's disease patients produces limited symptomatic relief. One approach to augment the outgrowth and function of nigral grafts includes exposure of the graphs to neurotrophic factors; however, the temporal requirements for optimizing these actions are unknown. The present study characterized the ontogeny of brain-derived neurotrophic factor (BDNF) in the rat striatum and used this information to define and evaluate three distinct periods of BDNF infusion into fetal nigral grafts transplanted into the striatum of rats with experimental Parkinson's disease. At postnatal day 1 (P1), BDNF and dopamine were measured at 17 and 27% of peak levels, respectively, that occurred at P27 for both. Both compounds showed their greatest surge between P7 and P20, increasing from 40% to approximately 95% of peak levels. Exogenous BDNF infused into transplants during weeks 1 and 2 after the transplantation, which coincide with the developmental period embryonic day 14 (E14)-P7 for transplanted tissue, did not improve rotational behavior or enhance fiber outgrowth of transplanted dopamine neurons. Delaying the BDNF infusion until transplanted tissue was approximately P8-P21 greatly enhanced the effect on rotational behavior and doubled the area of dopamine fiber outgrowth from the transplants. Delaying the infusion until transplanted tissue was approximately P36-P49 failed to augment fiber outgrowth and decreased the behavioral function of transplants. Thus, the optimal effect of exogenous BDNF on the development of dopamine neurons in fetal nigral transplants occurs at a postnatal age when endogenous dopamine and BDNF show the greatest increases during the normal development of the striatum.

Age-related decline in striatal dopamine release and motoric function in brown Norway/Fischer 344 hybrid rats.

The Brown Norway/Fischer 344 F1 hybrid rats (F344BNF1) is a newer rat model and is emerging as an important rodent model of aging. In the present study we used motoric performance tests, intracerebral microdialysis, and neurochemical measures of postmortem brain tissue to investigate the effects of aging in young (4-5 months), middle-aged (18-19), and old (24-25 months) F344BNF1 hybrid rats. We observed that old F344BNF1 rats exhibited decreased motoric performance, and lower levels of spontaneous and d-amphetamine-induced locomotor activity than those observed in young F344BNF1 rats. Microdialysis measures of extracellular basal levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 4-hydroxy-3-methoxyphenylacetic acid (HVA) were significantly diminished in the striata of the middle-aged and old rats as compared to levels in young animals. In addition, d-amphetamine-evoked overflow of DA was significantly decreased in the middle-aged and aged rat striatum as compared to DA overflow in young F344BNF1 rats. Studies of postmortem brain tissue showed that the changes in overflow of DA correlated with significantly lower DA tissue content in ventral striatum and midbrain. Moreover, both dopamine turnover ratios (DOPAC/DA, HVA/DA) and the serotonin turnover ratio (5-HIAA/5-HT) were significantly elevated in the ventral striatum and nucleus accumbens. The results of this study demonstrate a correlation between reductions in striatal DA neurochemistry and diminished motor function in aged F344BNF1 rats.

BDNF enhances the functional reinnervation of the striatum by grafted fetal dopamine neurons.

Transplantation of fetal dopaminergic neurons to the striatum can ameliorate neurological deficits exhibited by experimental animals and human graft recipients with Parkinson's disease. Recovery, however, is incomplete due to suboptimal survival of grafted cells and limited synaptic integration with the host brain. A number of neurotrophic factors have recently been shown to promote the survival and differentiation of dopamine neurons in vitro. In the present study we examined the effects of one such factor, brain-derived neurotrophic factor (BDNF), on the development of fetal substantia nigra following transplantation to the dopamine-depleted striatum of adult rats. Infusion of BDNF greatly enhanced the reinnervation of the host striatum by the engrafted dopamine neurons, as determined by tyrosine hydroxylase immunostaining, and also increased the effect of the graft on locomotor behavior induced by amphetamine administration. These effects became apparent during the 4-week period of BDNF infusion and persisted for an additional 6 weeks following the termination of BDNF delivery. These findings demonstrate that BDNF exerts a significant effect on the functional reinnervation of the striatum by transplanted fetal dopamine neurons in the rat, and suggest that application of this factor might similarly improve the clinical efficacy of neural transplantation employed in the treatment for Parkinson's disease.

Regional levels of lactate and norepinephrine after experimental brain injury.

The recently developed controlled cortical impact model of brain injury in rats may be an excellent tool by which to attempt to understand the neurochemical mechanisms mediating the pathophysiology of traumatic brain injury. In this study, rats were subjected to lateral controlled cortical impact brain injury of low grade severity; their brains were frozen in situ at various times after injury to measure regional levels of lactate, high energy phosphates, and norepinephrine. Tissue lactate concentration in the injury site left cortex was increased in injured animals by sixfold at 30 min and twofold at 2.5 h and 24 h after injury (p < 0.05). At all postinjury times, lactate concentration was also increased in injured animals by about twofold in the cortex and hippocampus adjacent to the injury site (p < 0.05). No significant changes occurred in the levels of ATP and phosphocreatine in most of the brain regions of injured animals. However, in the primary site of injury (left cortex), phosphocreatine concentration was decreased by 40% in injured animals at 30 min after injury (p < 0.05). The norepinephrine concentration was decreased in the injury site left cortex of injured animals by 38% at 30 min, 29% at 2.5 h, and 30% at 24 h after injury (p < 0.05). The level of norepinephrine was also reduced by approximately 20% in the cortex adjacent to the injury site in injured animals. The present results suggest that controlled cortical impact brain injury produces disorder in the neuronal oxidative and norepinephrine metabolism.

Intranigral injections of SCH 23390 inhibit SKF 82958-induced rotational behavior.

The selective D1 receptor antagonist, SCH 23390, was injected into the pars reticulata region of the lesioned substantia nigra at various concentrations (3.0, 1.5, 1.0, 0.6 or 0.3 mM) just before a s.c. injection of either the selective D1 agonist, SKF 82958; the selective D2 agonist, quinpirole; or the mixed D1-D2 receptor agonist, apomorphine. SCH 23390 pretreatment (1) had no significant effect on quinpirole rotational behavior, (2) attenuated apomorphine rotational behavior and (3) dose-dependently inhibited SKF 82958 rotational behavior with the highest SCH 23390 doses completely blocking SKF 82958 rotational behavior in some animals. These data provide further evidence that dopamine release in the midbrain may act as a neuromodulator of motor behavior, and that D1 receptors play a functional role in this process.

Intranigral injections of SCH 23390 inhibit amphetamine-induced rotational behavior.

Rats were given unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway and permanent indwelling cannula were surgically implanted into the non-lesioned side of the brain; cannula were used for direct injections of dopamine antagonists into the pars reticulata region of the non-lesioned substantia nigra. The selective D1 receptor antagonist, SCH 23390, was injected intranigrally at various concentrations (3.0, 1.5, 1.0, 0.6, or 0.3 mM) just prior to an intraperitoneal injection of amphetamine. SCH 23390 dose-dependently inhibited amphetamine-induced rotational behavior with the highest doses completely blocking rotational behavior in some animals. An intranigral injection of the selective D2 receptor antagonist, (-)-sulpiride (1.0 mM), did not produce a significant reduction in amphetamine-induced rotational behavior whereas an equivalent molar concentration of SCH 23390 (1.0 mM) produced a significant 62% reduction in amphetamine-induced rotational behavior. A concentration of SCH 23390 that produced a 50% reduction in rotational behavior when injected directly into the substantia nigra was unable to produce a significant reduction in rotational behavior when injected directly into the striatum. The effects of intranigral injections of SCH 23390 on apomorphine-induced rotational behavior were directly opposite to that observed for amphetamine-induced rotational behavior; contralateral rotational behavior increased relative to baseline measures. These data support the hypothesis that dopamine release in the midbrain may act as a neuromodulator of motor behavior, and that D1 receptors play a functional role in this process.