Elsevier

Life Sciences

Volume 127, 15 April 2015, Pages 82-89
Life Sciences

Cardiovascular and autonomic alterations in rats with Parkinsonism induced by 6-OHDA and treated with L-DOPA

https://doi.org/10.1016/j.lfs.2015.01.032Get rights and content

Abstract

Objective

Evaluate the effects caused by L-DOPA on cardiovascular and autonomic parameters in an animal model of Parkinsonism induced by 6-hydroxydopamine (6-OHDA).

Methods

Adult male Wistar rats were subjected to bilateral microinfusion of 6-OHDA or saline (sham group) in the substantia nigra, and treated by gavage with L-DOPA or water for 7 days after surgery. On the 6th day the rats were subjected to femoral artery catheterization for cardiovascular recording. Mean arterial pressure (MAP) and heart rate (HR) were evaluated at baseline and during head up tilt (HUT) protocol. Spectral analysis of cardiovascular variability was performed using the V2.4 CardioSeries software v2.4. The lesion was quantified by dopamine levels in the striatum.

Results

Dopamine levels in the striatum were decreased in 6-OHDA rats (sham: 4.79 ± 0.49 ng/mg; 6-OHDA: 1.99 ± 0.68 ng/mg) and were not recovered by Prolopa treatment. Baseline values of MAP and HR were not different between groups. HUT induced an increase in MAP and HR (ΔMAP: 17 ± 1 mm Hg, ΔHR: 39 ± 4 bpm) that were attenuated in 6-OHDA and in Prolopa treated animals. At baseline, the systolic arterial pressure (SAP) variance was lower in the 6-OHDA and sham Prolopa groups. Spontaneous baroreflex sensitivity was higher at baseline in the 6-OHDA group as compared to all studied groups.

Conclusions

Our data suggest that treatment with Prolopa did not interfere with cardiovascular variables at baseline. However, during HUT, the 6-OHDA and Prolopa control animals presented a lower cardiovascular compensation, suggesting a possible autonomic impairment in Parkinsonism induced by 6-OHDA.

Introduction

Clinically, Parkinson's disease (PD) is characterized by signs and symptoms such as bradykinesia, rigidity, tremor, and postural instability. It is a progressive neurodegenerative disease in which there is an irreversible loss of dopaminergic neurons in the substantia nigra pars compact (SNpc) located in the midbrain. This degeneration leads to functional changes in the basal ganglia (caudate and putamen), which are involved in controlling movement, resulting in the appearance of the main symptoms of this disease [16], [35].

Motor function is most noticeably affected in PD, but there are other symptoms associated with dysfunction of the autonomic nervous system, including cardiovascular disorders such as orthostatic hypotension (OH) [9], [48], [49]. These symptoms may be related to the involvement of the central nervous system as well as the peripheral postganglionic pathways of the autonomic nervous system [1], [15], [17]. It is still unknown whether drug treatments for PD can interact with the disease process, resulting in dysautonomia. The drugs used in the treatment of PD, including Prolopa, can cause cardiovascular disorders such OH [18], [26], [28], [29]. Thus, it is believed that the involvement of the autonomic nervous system in PD may result from the disease itself, medication use, or a combination of these factors [29], [42].

The administration of levodopa (L-DOPA; 3,4-dihydroxyphenylalanine) aims to restore the levels of dopamine (DA), which are compromised as a result of neurodegeneration [19], [39]. L-DOPA still remains the most effective drug for controlling the motor signs of PD [13], [30], but it also causes motor complications, particularly dyskinesias.

There is not yet an experimental model that represents all the manifestations of PD. We adopted the 6-OHDA (6-hydroxydopamine) model, which is a well-known classic model of Parkinsonism. The greatest degeneration of dopaminergic neurons is observed in the ventral region of the midbrain [11], [21], [40].

Postural changes such as the head-up tilt (HUT) result in the displacement of blood to the lower limbs, decreasing blood flow to the head. This condition requires compensatory adjustments that, if they do not occur promptly, can lead to a drop in blood pressure. This can cause symptoms such as orthostatic intolerance and even a sudden loss of consciousness [43]. Modulation by the autonomic nervous system ensures an adequate cardiac output in response to fluctuations in blood volume imposed by having an upright posture. In conditions such as PD, autonomic dysfunction may interfere with circulatory homeostasis, leading to OH [41], [46].

This study aimed to evaluate the effect of treatment with L-DOPA (Prolopa) on cardiovascular and autonomic parameters at baseline as well as during a HUT experiment in rats with Parkinsonism induced by 6-OHDA.

Section snippets

Animals

This work was conducted at the Department of Physiological Sciences (CIF) of the State University of Londrina (UEL) Center of Biological Sciences (CCB). Adult male Wistar rats weighing between 280–320 g at the start of the experiment were used. The animals were housed in polypropylene cages (45 × 25 × 25 cm) in a temperature-controlled room (22 ± 2 °C) into light/dark cycle of 12/12 h with food and water ad libitum. The procedures used were approved by the Ethics Committee on Animal Experimentation of

Analysis of DA in the striatum

The analysis of DA levels (Fig. 1) indicates that striatal DA levels in the 6-OHDA groups (water-treated: 1.99 ± 0.68 ng/mg; Prolopa-treated: 1.10 ± 0.32 ng/mg) showed a decrease when compared to the sham groups (water-treated: 4.79 ± 0.49 ng/mg; Prolopa-treated: 3.92 ± 0.58 ng/mg). These results indicate that the 6-OHDA-infused animals showed a greater than 50% loss of DA, confirming that the injury did not recover following treatment with Prolopa.

Baseline cardiovascular parameters

The analysis of the effect of treatment with water or

Discussion

Our data showed that the model of Parkinsonism induced by 6-OHDA did not promote baseline cardiovascular changes, nor did treatment with Prolopa. However, during HUT, cardiovascular compensation was attenuated in rats with 6-OHDA lesions or those treated with Prolopa. In addition, the SAP variance was decreased in the 6-OHDA and Prolopa groups, suggesting that under conditions where the sympathetic nervous system is recruited, the 6-OHDA lesion or treatment with Prolopa may contribute to the

Conclusion

The present study provides suggestive but inconclusive evidence that in Parkinsonism induced by 6-OHDA, as well as with the use of the classic PD treatment L-DOPA, there are detrimental effects on cardiovascular variables. These effects are particularly evident when studying phasic alterations involving the sympathetic nervous system, for example HUT, and may lead to disorders of hemodynamic dysfunction such as OH.

Conflict of interest statement

The authors declare no conflicts of interest.

Acknowledgment

The authors wish to thank Elizabeth Zocal for the laboratory technique, which helped us determine the levels of dopamine. The authors also thank the CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) for the fellowship to Aline Santana da Silva and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) for the fellowship to Marli Cardoso Martins-Pinge.

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