Levodopa/Benserazide PLGA Microsphere Prevents L-Dopa-Induced Dyskinesia via Lower ß-Arrestin2 in 6-Hydroxydopamine Parkinson's Rats.

Prolonged pulsatile administration of Levodopa (L-dopa) can generate L-dopa-induced dyskinesia (LID). Numerous research has reported that continuous dopamine delivery (CDD) was useful in reducing the severity of LID. 6-OHDA lesioned rats were divided into two groups to receive intermittent L-dopa stimulation (L-dopa/benserazide) or Levodopa/benserazide PLGA microsphere (LBPM) for 3 weeks. rAAV (recombinant adeno-associated virus) vector was used to overexpress and ablation of ß-arrestin2. We found that LBPM developed less AIM severity compared with standard L-dopa administration, whereas selective deletion of ß-arrestin2 in striatum neurons dramatically enhanced the severity of dyskinesia by LBPM. On the contrary, the effects of LBPM in terms of ALO AIM were further relieved by ß-arrestin2 overexpression. Furthermore, no significant change in motor behavior was seen either in inhibition or overexpression of ß-arrestin2. In short, our experiments provided evidence that LBPM's prevention of LID behavior was likely due to ß-arrestin2, suggesting that a therapy modulating ß-arrestin2 may offer a more efficient anti-dyskinetic method with a low risk of untoward effects.

Lipoic acid alleviates L­DOPA­induced dyskinesia in 6­OHDA parkinsonian rats via anti­oxidative stress.

Levodopa (L­DOPA) is the gold standard for symptomatic treatment of Parkinson's disease (PD); however, long­term therapy is associated with the emergence of L­DOPA­induced dyskinesia (LID). Nigral dopaminergic cell loss determines the degree of drug exposure and time required for the initial onset of LID. Accumulating evidence indicates that α­lipoic acid (ALA) decreases this nigral dopaminergic cell loss. However, until now, the precise mechanisms of ALA have only been partially understood in LID. Chronic L­DOPA treatment was demonstrated to develop intense AIM scores to assess dyskinetic symptoms. Rats in the LID group were administrated twice daily with L­DOPA + benserazide for 3 weeks to induce a rat model of dyskinesia. Moreover, other 6­OHDA­lesioned rats were treatment with ALA (31.5 mg/kg or 63 mg/kg) in combination with L­DOPA treatment. Furthermore, the authors investigated the level of malondialdehyde (MDA) and glutathione (GSH) activity, as well as IBa­1, caspase­3 and poly (ADP-ribose) polymerase (PARP) in substantia nigra by the way of western blotting and immunofluorescence. ALA reduced LID in a dose­dependent manner without compromising the anti­PD effect of L­DOPA. Moreover, ALA reduced the level of MDA and upregulated the GSH activity, as well as ameliorated IBa­1 positive neurons in the substantia nigra. Finally, it was identified that ALA could reduce L­DOPA­induced cleaved­caspase­3 and PARP overexpression in the substantia nigra. Based on the present findings, ALA could be recommended as a promising disease­modifying therapy when administered with L­DOPA early in the course of PD. The exact mechanism for this action, although incompletely understood, appears to relate to anti­oxidative stress and anti­apoptosis.

Antidyskinetic Treatment with MTEP Affects Multiple Molecular Pathways in the Parkinsonian Striatum.

Parkinson's disease is characterized by dopaminergic neuron loss and dopamine (DA) depletion in the striatum. Standard treatment is still focused on the restoration of dopamine with exogenous L-Dopa, which however causes L-Dopa-induced dyskinesia (LID). Several studies have shown that antagonism of the metabotropic glutamate receptor 5 alleviates LID, but the underlying mechanisms have remained unclear. We set out to determine where this alleviation may depend on restoring the equilibrium between the two main striatofugal pathways. For this purpose, we examined molecular markers of direct and indirect pathway involvement (prodynorphin and proenkephalin, resp.) in a rat model of LID treated with the mGluR5 antagonist MTEP. Our results show that MTEP cotreatment significantly attenuates the upregulation of prodynorphin mRNA induced by L-Dopa while also decreasing the expression levels of proenkephalin mRNA. We also examined markers of the mGluR5-related PKC/MEK/ERK1/2 signaling pathway, finding that both the expression of PKC epsilon and the phosphorylation of MEK and ERK1/2 had decreased significantly in the MTEP-treated group. Taken together, our results show that pharmacological antagonism of mGluR5 normalizes several abnormal molecular responses in the striatum in this experimental model of LID.

Current Experimental Studies of Gene Therapy in Parkinson's Disease.

Parkinson's disease (PD) was characterized by late-onset, progressive dopamine neuron loss and movement disorders. The progresses of PD affected the neural function and integrity. To date, most researches had largely addressed the dopamine replacement therapies, but the appearance of L-dopa-induced dyskinesia hampered the use of the drug. And the mechanism of PD is so complicated that it's hard to solve the problem by just add drugs. Researchers began to focus on the genetic underpinnings of Parkinson's disease, searching for new method that may affect the neurodegeneration processes in it. In this paper, we reviewed current delivery methods used in gene therapies for PD, we also summarized the primary target of the gene therapy in the treatment of PD, such like neurotrophic factor (for regeneration), the synthesis of neurotransmitter (for prolong the duration of L-dopa), and the potential proteins that might be a target to modulate via gene therapy. Finally, we discussed RNA interference therapies used in Parkinson's disease, it might act as a new class of drug. We mainly focus on the efficiency and tooling features of different gene therapies in the treatment of PD.

Inhibition of Glycogen Synthase Kinase-3ß (GSK-3ß) as potent therapeutic strategy to ameliorates L-dopa-induced dyskinesia in 6-OHDA parkinsonian rats.

Levodopa (L-dopa) is the dominating therapy drug for exogenous dopaminergic substitution and can alleviate most of the manifestations of Parkinson's disease (PD), but long-term therapy is associated with the emergence of L-dopa-induced dyskinesia (LID). Evidence points towards an involvement of Glycogen Synthase Kinase-3ß (GSK-3ß) in development of LID. In the present study, we found that animals rendered dyskinetic by L-dopa treatment, administration of TDZD8 (2mg/kg) obviously prevented the severity of AIM score, as well as improvement in motor function (P < 0.05). Moreover, the TDZD8-induced reduction in dyskinetic behavior correlated with a reduction in molecular correlates of LID. TDZD8 reduced the phosphorylation levels of tau, DARPP32, ERK and PKA protein, which represent molecular markers of LID, as well as reduced L-dopa-induced FosB mRNA and PPEB mRNA levels in the lesioned striatum. In addition, we found that TDZD8 antidyskinetic properties were overcome by D1 receptor, as pretreatment with SKF38393 (5 mg/kg, 10 mg/kg, respectively), a D1 receptor agonist, blocked TDZD8 antidyskinetic actions. This study supported the hypothesis that GSK-3ß played an important role in the development and expression of LID. Inhibition of GSK-3ß with TDZD8 reduced the development of ALO AIM score and associated molecular changes in 6-OHDA-lesioned rats.

Intraneuronal accumulation of Aß42 induces age-dependent slowing of neuronal transmission in Drosophila.

Beta amyloid (Aß42)-induced dysfunction and loss of synapses are believed to be major underlying mechanisms for the progressive loss of learning and memory abilities in Alzheimer's disease (AD). The vast majority of investigations on AD-related synaptic impairment focus on synaptic plasticity, especially the decline of long-term potentiation of synaptic transmission caused by extracellular Aß42. Changes in other aspects of synaptic and neuronal functions are less studied or undiscovered. Here, we report that intraneuronal accumulation of Aß42 induced an age-dependent slowing of neuronal transmission along pathways involving multiple synapses.