Behavioral, Neurochemical and Histological Alterations Promoted by Bilateral Intranigral Rotenone Administration: A New Approach for an Old Neurotoxin

Abstract

Rotenone exposure in rodents provides an interesting model for studying mechanisms of toxin-induced dopaminergic neuronal injury. However, several aspects remain unclear regarding the effects and the accuracy of rotenone as an animal model of Parkinson's disease (PD). In order to counteract these limitations, this study characterized a precise neurotoxin-delivery strategy employing the bilateral intranigral administration protocol of rotenone as a reliable model of PD. We performed bilateral intranigral injections of rotenone (12 μg) and subsequent general activity (1, 10, 20, and 30 days after rotenone) and cognitive (7, 8, 15, and 30 days after rotenone) evaluations followed by neurochemical and immunohistochemical tests. We have observed that rotenone was able to produce a remarkable reduction on the percentage of tyrosine hydroxylase immunoreactive neurons (about 60%) within the substantia nigra pars compacta. Dopamine (DA) was severely depleted at 30 days after rotenone administration, similarly to its metabolites. In addition, an increase in DA turnover was detected at the same time-point. In parallel, striatal serotonin and its metabolite were found to be increased 30 days after the neurotoxic insult, without apparent modification in the serotonin turnover. Besides, motor behavior was impaired, mainly 1 day after rotenone. Furthermore, learning and memory processes were severely disrupted in different time-points, particularly at the training and test session (30 days). We now provide further evidence of a time-dependent neurodegeneration associated to cognitive impairment after the single bilateral intranigral administration of rotenone. Thus, it is proposed that the current rotenone protocol provides an improvement regarding the existing rotenone models of PD.

REM sleep deprivation generates cognitive and neurochemical disruptions in the intranigral rotenone model of Parkinson's disease

“…In this model, a massive inhibition of mitochondrial complex I produces selective degeneration of the dopaminergic nigrostriatal system and reproduces key pathological features of clinical PD (Sherer et al, ; Alam and Schmidt, ). The present study showed that intranigral rotenone did not altered the motor parameters at the time points analyzed, corroborating our recent findings (Moreira et al, ). However, REMSD elicited an increase of ambulatory distance per se and also generated an increment in this parameter of the rotenone REMSD compared with the sham control group.…”

“…In fact, this neurotransmitter was intensely modulated by REMSD and rotenone. That is, striatal DA levels were reduced after rotenone, supporting recent findings (Santiago et al, ; Moreira et al, ). In addition, REMSD also caused an increment in DOPAC, HVA, and in DA turnover, which could be interpreted as an attempt to compensate for this increased neurotransmitter degradation, which is a classical mechanism of plasticity, also observed with neurotoxins (Hsieh et al, ; Ariza et al, ; Barbiero et al, ).…”

“…To test this rationale, we used the intranigral rotenone model of PD (Saravanan et al, 2005;Santiago et al, 2010), destroying up to 60% of the dopaminergic neurons located at the SNpc (Moreira et al, 2012). The REMSD protocol was used to modulate serotoninergic (Asikainen et al, 1997) and dopaminergic (Lima et al, 2012c) neurotransmission.…”

Unexpected Improvements of Spatial Learning and Memory Abilities in Chronic Rotenone Intoxicated Mice

“…We noted the impairment of motor coordination in rotenone-treated-group for 3 months, as well as alpha-synuclein inclusions in the dopaminergic neurons of the SN pc . These results suggested chronic intragastrical administrated rotenone replicated successfully the classical features of PD in the present study, which conformed to other reports [26], [27]. Rotenone can induce gastrointestinal tract dysfunction as determined by alpha-synuclein aggregation in the enteric nervous system (ENS), loss of myenteric neurons of the small intestine [28], a delay in gastric emptying, and impaired functioning of inhibitory neurons in the ENS [29].…”

Potential neuroprotective effect of androst‐5‐ene‐3β, 17β‐diol (ADIOL) on the striatum, and substantia nigra in Parkinson's disease rat model

“…Consistently, the present study revealed that DA content as well as the metabolites; DOPAC and HVA levels were reduced in the striatum of ROT‐treated rats with increase in the DA turnover supporting by the studies of Moreira et al () and Tong et al ().…”