Efficacy of Brain‐Derived Neurotrophic Factor and Neurotrophin‐3 on Neurochemical and Behavioral Deficits Associated with Partial Nigrostriatal Dopamine Lesions

Abstract

Brain‐derived neurotrophic factor (BDNF) promotes the survival of dopamine (DA) neurons, enhances expression of DA neuron characteristics, and protects these cells from 6‐hydroxydopamine (6‐OHDA) toxicity in vitro. We tested the ability of BDNF or neurotrophin‐3 (NT‐3) to exert similar protective effects in vivo during chronic delivery of 6‐OHDA to the rat neostriatum. Chronic infusions of BDNF or NT‐3 (12 µg/day) above the substantia nigra were started 6 days before and continued during an 8‐day chronic intrastriatal infusion of 6‐OHDA. In control and neurotrophin‐treated animals, 6‐OHDA treatment selectively depleted 50–60% of nigrostriatal DA nerve terminals but produced little if any loss of pars compacta DA cell bodies. This partial DA lesion resulted in three rotations per minute toward the lesioned hemisphere after treatment with the DA release‐inducing drug d‐amphetamine. Compared with supranigral infusions of vehicle, BDNF and NT‐3 decreased the number of these ipsiversive rotations by 70 and 48% and increased by 20‐ and 10‐fold, respectively, the number of contraversive rotations observed after amphetamine injection. When challenged with the DA receptor agonist apomorphine, BDNF‐ and NT‐3‐treated animals also exhibited a seven‐ and 3.5‐fold increase in the number of contraversive rotations relative to the vehicle group, respectively. Compared with vehicle, BDNF increased striatal levels of homovanillic acid (HVA; 86%), 3,4‐dihydroxyphenylacetic acid (DOPAC; 42%), and 5‐hydroxyindoleacetic acid (5‐HIAA; 32%) and the HVA/DA (43%) and 5‐HIAA/serotonin (34%) ratios in the DA‐denervated striatum. NT‐3 augmented only striatal 5‐HIAA levels (24%). Neither factor altered the 6‐OHDA‐induced decrease in striatal DA levels or high‐affinity DA uptake and thus did not protect against the destruction of DA terminals and did not alter striatal D1 or D2 ligand binding. Choline, GABA, and glutamate uptake in the striatum were not altered by the lesion or neurotrophin treatment. Thus, BDNF and to a lesser extent NT‐3 reverse rotational behavioral deficits and augment striatal DA and 5‐HT metabolism in a partial DA lesion model.

LY503430, a Novel α-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid Receptor Potentiator with Functional, Neuroprotective and Neurotrophic Effects in Rodent Models of Parkinson's Disease

“…Our in-house comparisons indicate, however, that LY503430 provides superior protection to all these other pharmacological interventions. We have not evaluated central administration of growth factors, but, for example, GDNF is effective in both nigral and striatal 6-OHDA lesion models (Altar et al, 1992(Altar et al, , 1994Rosenbald et al, 2000). In addition, in the current studies we observed an increased level of BDNF immunoreactivity in the substantia nigra after LY503430 treatment in the 6-OHDA-lesioned animals.…”

“…Many investigators have reported that glial derived growth factor (GDNF) promotes dopamine neuron survival (Tomac et al, 1995;Gash et al, 1996;Rosenbald et al, 2000), whereas other studies have shown that brain-derived growth factor (BDNF) can protect against behavioral, biochemical, and immunocytochemical changes after nigrostriatal dopamine lesions (Altar et al, 1992(Altar et al, , 1994Klein et al, 1999). A major drawback of growth factors is their large size and therefore the need to administer these molecules directly into the brain.…”

Ontogenic cell death in the nigrostriatal system

“…Supranigral infusion of BDNF was subsequently shown to reverse behavioral and biochemical deficits induced by intrastriatal infusion of 6OHDA (Altar et al 1994). However, BDNF did not protect mesencephalic dopamine neurons from axotomy (Knusel et al 1992;Lapchak et al 1993).…”

Neuregulins, Neuroprotection and Parkinson's Disease

“…Moreover, infusion of BDNF into the SN before or during chronic intrastriatal infusion of 6-OHDA does not prevent the loss of dopaminergic terminals in the striatum and does not protect against a partial loss of nigral dopamine neurons, but does reverse rotational behavior and augments dopamine metabolism (7). Delivery of BDNF, intracerebroventricularly or direcdy into brain tissue, shows relatively poor tissue penetration and diffusion when compared to other neurotrophins (e.g., NT-3 or NGF) (9), due in large part to the ubiquitous presence of both catalytic and non-catalytic trkB receptors throughout the brain.…”

“…NT-3 decreases body weight during chronic infusion periods, increases the frequency of amphetamine-induced contraversive rotational behavior, and attenuates amphetamine-induced locomotor activity (115). Infusion of NT-3 into the SN before and during a chronic intrastriatal infusion of 6-OHDA does not prevent the loss of dopaminergic terminals in the striatum and does not protect against a partial loss of nigral dopamine neurons, but does reverse rotational behavior and augments dopamine metabolism (7). Notably, infusion of NT-3 into the SN immediately after transection of the ipsilateral nigrostriatal pathway is less potent at promoting the survival of dopamine neurons than BDNF, but completely preserves TH expression (67).…”