Ameliorating effects of curcumin on 6-OHDA-induced dopaminergic denervation, glial response, and SOD1 reduction in the striatum of hemiparkinsonian mice.

BACKGROUND: Inflammation and oxidative stress are believed to contribute to neuronal degeneration of the nigrostriatal dopaminergic (DA) pathway in Parkinson's disease. Curcumin, a component of the yellow curry spice, has been reported possessing anti-inflammatory and anti-oxidative effects. AIM: The present study investigated the effects of curcumin on the extent of DA innervation, glial response, and Cu/Zn superoxide dismutase (SOD1) expression in the striatum of 6-hydroxydopamine (6-OHDA)-lesioned mice. MATERIALS AND METHODS: 6-OHDA was unilaterally injected into the right striatum of ICR male mice. Curcumin (200 mg/kg) was administered daily for 7 days starting instantaneously after 6-OHDA injection. Seven days after 6-OHDA insult, mice were euthanized and striatal sections were collected, immunohistochemically stained, and quantitated for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), ionized calcium binding adapter molecule 1 (Iba1), and SOD1 immunoreactivity. RESULTS: 6-OHDA injection triggered a significant loss of TH-immunoreactive (-IR) axons, induced reaction of GFAP-IR astrocytes and Iba1-IR microglia, and decreased SOD1 expression in the 6-OHDA-lesioned striatum. Curcumin attenuated loss of TH-IR fibers, diminished activation of astrocytes and microglia, and sustained SOD1 level in the lesioned striatum. CONCLUSIONS: These results suggest that curcumin counteracts the neurotoxicity of 6-OHDA through its anti-inflammatory properties (inhibition of glial response) and preservation of SOD1 expression.

D2 Dopamine receptor blockade results in sprouting of DA axons in the intact animal but prevents sprouting following nigral lesions.

Recently it was demonstrated that sprouting of dopaminergic neurons and a microglial and astrocyte response follows both partial lesions of the substantia nigra pars compacta and blockade of the D2 dopamine receptor. We therefore studied the effects of the combination of these two treatments (lesioning and D2 dopamine receptor blockade). Haloperidol administration caused a 57% increase in dopaminergic terminal tree size (measured as terminal density per substantia nigra pars compacta neuron) and an increase of glia in the striatum. Following small to medium nigral lesions (less than 60%), terminal tree size increased by 51% on average and returned density of dopaminergic terminals to normal. In contrast, administration of haloperidol for 16 weeks following lesioning resulted in reduced dopaminergic terminal density and terminal tree size (13%), consistent with absent or impaired sprouting. Glial cell numbers increased but were less than with lesions alone. When haloperidol was administered after the striatum had been reinnervated through sprouting (16-32 weeks after lesioning), terminal tree size increased up to 150%, similar to the effect of haloperidol in normal animals. By examining the effect of administering haloperidol at varying times following a lesion, we concluded that a switch in the effect of D2 dopamine receptor blockade occurred after dopaminergic synapses began to form in the striatum. We postulate that when synapses are present, D2 dopamine receptor blockade results in increased terminal density, whereas prior to synapse formation D2 dopamine receptor blockade causes attenuation of a sprouting response. We speculate that D2 dopamine receptors located on growth cones 'push' neurites toward their targets, and blockade of these receptors could lead to attenuation of sprouting.