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melior melior melior discovery melior pharmaceuticals preclinical services pre-clinical services in vivo pharmacology in vivo efficacy efficacy models pharmacokinetics indications discovery specialized animal models bioanalytical services theratrace exton pennsylvania cro contract research drug discovery drug development metabolic disease alzheimer’s alzheimers diabetes reprofiling

Melior Discovery neurology

6-OHDA Rat Model of Parkinson's Disease
The neurotoxin 6-hydroxydopamine (6-OHDA) is widely used to induce depletion of dopaminergic neurons in animal models of Parkinson's Disease (PD).  Unilateral administration of 6-OHDA into the medial forebrain bundle can produce a 90-95% ipsilateral depletion of dopamine neurons in 80-90% of animals injected, leading to a PD - like motor dysfunction. 

                          

Striatal dopamine was significantly reduced in vehicle and L-DOPA treated animals compared to unlesioned (untreated) animals in the ipsilateral region relative to lesion site.  Dopamine was also significantly reduced in ipsilateral regions compared to contralateral regions in both vehicle and L-DOPA treated animals.  Data are ± SEM; *p<0.05, **p<0.01, compared to ipsilateral unlesioned animals; ###p<0.001 compared to contralateral vehicle and L-DOPA treated animals. 

 

Lesioned rats that passed amphetamine rotational testing to verify lesion severity were then primed with L-DOPA.  Chronic treatment with L-DOPA produces abnormal involuntary movements (AIMs) called L-DOPA-induced dyskinesia (LID), similar to the symptoms seen in PD patients.  Rats were evaluated for dyskinesia including axial, limb and orolingual AIMs.  Although amantadine is used in PD patients to treat LID, it is not currently FDA approved for treatment of dyskinesia. 

                              

Once daily administration of amantadine (40mg/kg) significantly reduces AIMs score on day 12 of dosing.  Data are mean ± SEM; **p<0.01 compared to vehicle.  Scores represent the sum of axial, limb and orolingual AIMs at multiple time points over a two hour observation period. 

 

In addition to AIMs testing, Forepaw Adjusting Steps (FAS) testing was conducted over a series of trials to quantify the number of adjusting steps for both paws in the forehand and backhand directions of movement.  This test is used to assess motor deficits in the forelimbs analogous to limb akinesia and gait problems in PD patients.  Lesioned rats show a unilateral motor deficit in adjusting steps compared to unlesioned animals.  Chronic treatment with L-DOPA can improve this function, and it is important to determine if a treatment interferes with this L-DOPA effect. 

                                                   

Once daily administration of amantadine (40mg/kg) did not interfere with L-DOPA efficacy, and slightly improved percentage of forepaw adjusting steps on day 11 compared to vehicle.  Data are mean ± SEM. 

 

If you are interested in learning more about the 6-OHDA Rat Model of Parkinson's Disease, please contact models@meliordiscovery.com to start the conversation.