Monday, May 17, 2010

Fluoxetine May Reverse Neuronal Loss in Parkinson's Disease

http://www.odec.ca/projects/2004/mcgo4s0/public_html/t4/Brainpet.gif

This is a rather interesting study of the loss of dopaminergic neurons in Parkinson's Disease - using a rat brain model - and that it may be reversible with fluoxetine (Prozac). The basic message seems to this:
Taken all together, the past and present results indicate that SSRIs such as fluoxetine may delay or prevent the onset of PD in patients with prodromal non-motor symptoms. A randomized, double-blind, placebo-controlled study of SSRIs in the prodromal non-motor symptoms of PD is needed to confirm our hypothesis.
Suzuki K, Okada K, Wakuda T, Shinmura C, Kameno Y, et al. (2010). Destruction of Dopaminergic Neurons in the Midbrain by 6-Hydroxydopamine Decreases Hippocampal Cell Proliferation in Rats: Reversal by Fluoxetine. PLoS ONE 5(2): e9260. doi:10.1371/journal.pone.0009260

The whole article is available by following the link.

Here is the abstract:

Abstract

Background

Non-motor symptoms (e.g., depression, anxiety, and cognitive deficits) in patients with Parkinson disease (PD) precede the onset of the motor symptoms. Although these symptoms do not respond to pharmacological dopamine replacement therapy, their precise pathological mechanisms are currently unclear. The present study was undertaken to examine whether the unilateral 6-hydroxydopamine (6-OHDA) lesion to the substantia nigra pars compacta (SNc), which represents a model of long-term dopaminergic neurotoxicity, could affect cell proliferation in the adult rat brain. Furthermore, we examined the effects of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the selective noradrenaline reuptake inhibitor maprotiline on the reduction in cell proliferation in the subgranular zone (SGZ) by the unilateral 6-OHDA lesion.

Methodology/Principal Findings

A single unilateral injection of 6-OHDA into the rat SNc resulted in an almost complete loss of tyrosine hydroxylase (TH) immunoreactivity in the striatum and SNc, as well as in reductions of TH-positive cells and fibers in the ventral tegmental area (VTA). On the other hand, an injection of vehicle alone showed no overt change in TH immunoreactivity. A unilateral 6-OHDA lesion to SNc significantly decreased cell proliferation in the SGZ ipsilateral to the 6-OHDA lesion, but not in the contralateral SGZ or the subventricular zone (SVZ), of rats. Furthermore, subchronic (14 days) administration of fluoxetine (5 mg/kg/day), but not maprotiline significantly attenuated the reduction in cell proliferation in the SGZ by unilateral 6-OHDA lesion.

Conclusions/Significance

The present study suggests that cell proliferation in the SGZ of the dentate gyrus might be, in part, under dopaminergic control by SNc and VTA, and that subchronic administration of fluoxetine reversed the reduction in cell proliferation in the SGZ by 6-OHDA. Therefore, SSRIs such as fluoxetine might be potential therapeutic drugs for non-motor symptoms as well as motor symptoms in patients with PD, which might be associated with the reduction in cell proliferation in the SGZ.

My initial reaction on reading this was that it was funding by one of the pharmaceutical companies - but that seems not to be the case.

Funding: This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan to Drs. N. Mori (#19209039) and T. Wakuda (#19591347). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

I want to also include the discussion section, where the "meat" of the article resides.

Discussion

The major findings of the present study are that a unilateral 6-OHDA lesion to the SNc in rat significantly decreased cell proliferation in the SGZ ipsilateral to the lesion, but not in the contralateral SGZ or SVZ, and that subchronic (14 days) administration of fluoxetine, but not maprotiline, significantly attenuated the reduction in cell proliferation in the SGZ by unilateral 6-OHDA lesion. This is a first report to demonstrate that a unilateral 6-OHDA lesion to SNc caused a reduction of cell proliferation in the SGZ ipsilateral, but not contralateral, to the lesion. These findings suggest that cell proliferation in the SGZ might be, in part, under dopaminergic control from SNc and VTA since the hippocampus receives dopaminergic input from both [31][33].

Accumulating evidence suggests that dopamine is a potent stimulator of endogenous neural precursor cell proliferation in the SVZ and SGZ in the adult brain [26][30], [34]. Höglinger et al. [28] reported the effect of dopaminergic denervation on cell proliferation in the SVZ and SGZ in the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri​dine (MPTP)-treated mice, an animal model of PD. MPTP (four injections of 10 mg/kg at 2-hour intervals) induced a complete loss of dopaminergic fibers in the SNc that fully recovered within 70 days. Cell proliferation in the SGZ first decreased and then recovered in parallel with dopaminergic denervation and reinnervation, respectively [28]. There is also a close anatomical relationship between afferent dopaminergic fibers and proliferating cells to be preserved in the SVZ of non-human primates [27]. Interestingly, the reduction in the number of proliferating precursor cells in the SVZ and SGZ of postmortem brain tissue from patients with PD was reported [28]. Furthermore, Hiramoto et al. [35] reported that dopamine receptor agonist apomorphine increased the number of BrdU-positive cells in SGZ, and that dopamine D2 receptor antagonist blocked the increase in BrdU-positive cells by apomorphine, suggesting that the stimulation of dopamine D2 receptors can increase cell proliferation in the SGZ. Taken together, the results suggest it is likely that cell proliferation in the SGZ of the dentate gyrus might be under dopaminergic control.

Freundlieb et al. [27] reported the existence of a topographically organized dopaminergic projection from the SNc to the SVZ in aged primates. MPTP treatment (four to six MPTP injections per animal; cumulative dose, 1.2–2.0 mg/kg) caused a significant decrease in the number of proliferating cells in the denervated regions of the SVZ, suggesting that an intact dopaminergic nigro-subventricular innervation is crucial for sustained neurogenesis in aged primates [27]. However, in the present study we found no alteration in the number of proliferating cells in the SVZ of adult rat brain after ipsilateral 6-OHDA lesioning. The precise reasons underlying the difference between the two studies are currently unknown. One possibility may be the differences in the degenerative profile (systemic MPTP injection (complete lesion model) vs. ipsilateral 6-OHDA lesion (partial lesion model)). Another possibility is that the intact dopaminergic neurons on the contralateral side may compensate for dopaminergic transmission to SVZ, although further study is necessary.

As mentioned, we observed that subchronic (14 days) administration of fluoxetine (5 mg/kg/day) significantly attenuated the reduction in cell proliferation in the SGZ ipsilateral to the 6-OHDA lesion, but not in the contralateral SGZ or in control rats. To the best of our knowledge, this is the first report of a beneficial effect of an SSRI on the reduction in cell proliferation induced by dopaminergic lesioning of the midbrain in the adult rodent hippocampus. Malberg and Duman [36] reported that cell proliferation in the adult hippocampus is decreased by inescapable stress, and that fluoxetine treatment (10 mg/kg b.i.d. for 7 days) blocked the downregulation of cell proliferation resulting from inescapable stress. Furthermore, repeated treatment with fluoxetine (10 mg/kg/day for 10 days) could reverse the reduction in the number of proliferating cells in the SGZ of streptozotocin (STZ)-induced diabetic mice, but not control mice [37]. Thus, it should be noted that fluoxetine can reverse the reduction in cell proliferation in the SGZ by 6-OHDA lesion, stress, or STZ. In contrast, some other reports showed that chronic administration of fluoxetine increased the number of cell proliferation in the SGZ of control rats [38][42], which is inconsistent with the present results. It seems that treatment schedule (e.g., dose, treatment interval) may contribute to this discrepancy, although the precise reasons underlying the discrepancy are currently unclear.

In this study, we found that, in Morris water maze task, 6-OHDA lesioning did not develop non-motor symptoms (e.g., learning and memory), suggesting that unilateral reduction in the hippocampal neurogenesis by the hemispheric dopaminergic deprivation may not be sufficient to develop behavioral non-motor symptoms (e.g., cognitive deficits). The aforementioned findings suggest that the reduction of cell proliferation in the SGZ of the adult hippocampus may be involved in the non-motor symptoms (e.g., depression, anxiety, and cognitive deficits) as well as in the motor symptoms in patients with PD. Considering the beneficial effects of SSRIs (e.g., fluoxetine) in the regulation of cell proliferation in the SGZ, it seems that SSRIs such as fluoxetine would be potential therapeutic drugs for PD. Some papers have demonstrated that antidepressants such as SSRIs are effective in the treatment of depression in patients with PD [14][18]. Non-motor symptoms may develop many years, even decades, before the onset of PD [11][13], suggesting these neuropsychiatric symptoms are risk factors for the development of PD. Taken all together, the past and present results indicate that SSRIs such as fluoxetine may delay or prevent the onset of PD in patients with prodromal non-motor symptoms. A randomized, double-blind, placebo-controlled study of SSRIs in the prodromal non-motor symptoms of PD is needed to confirm our hypothesis.

It is known that noradrenergic innervation that originates in the locus coeruleus terminates diffusely throughout the hippocampus, and one of subregions where the highest density occurs is the just inferior to the granular cell layer of dentate gyrus. Since anti-TH immunohistochemistry recognizes noradrenergic fibers, the reduction in TH immunoreactivity in the hilus of 6-OHDA treated rats (Fig. 2L) indicates that noradrenergic as well as dopaminergic inputs to the hippocampus have been affected by 6-OHDA treatment in our study. Axons of the locus coeruleus project to the hippocampus via the dorsal bundle, which ascends to traverse the midbrain tegmentum [43]. Due to our coordinate for the stereotaxic injection, which had intended to avoid the hippocampal injury, 6-OHDA solution along the needle track might have affected noradrenergic axons in the vicinity of the injection site. Therefore, the finding suggests that decrease in hippocampal neurogenesis might be a result from not only dopaminergic destruction but also reduction of noradrenergic inputs to the hippocampus by intra-SNc 6-OHDA. From the clinical viewpoint, the locus coeruleus appears to be constantly affected in PD, as witnessed by the extensive cell loss occurring PD patients [44][46]. Noradrenaline levels in several brain regions of PD patients have been shown to be significantly reduced [47]. Therefore, the ameliorating effect of SSRI on the decrease in hippocampal neurogenesis after 6-OHDA treatment implies that SSRI would be beneficial for PD patients who have deficiency in both dopaminergic and noradrenergic systems.

In conclusion, the present study suggests that cell proliferation in the SGZ of the dentate gyrus of the adult rat brain might be under dopaminergic control from SNc and VTA. Additionally, SSRIs such as fluoxetine potentially are therapeutic drugs for non-motor symptoms as well as motor symptoms in patients with PD, since fluoxetine can reverse the downregulation of cell proliferation in the SGZ by 6-OHDA lesion.


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