In Mice and Men (and Women): Prostate Drug, Terazosin to Slow Progression of Parkinson’s Disease

        In 1817, English physician James Parkinson published “An Essay on the Shaking Palsy,” which was the earliest known comprehensive explanation of Parkinson’s Disease (PD). Over 200 years later the underlying basis causing PD remains a mystery. However, research suggests that PD is a consequence of the complex, multifaceted relationship between several environmental and genetic components.¹ Leucine-rich repeat kinase 2 (LRRK2) is a kinase enzyme encoded by the LRRK2 gene. Mutations or variations of the LRRK2 gene have been deemed as the principle factor manipulating the genome in most cases of familial PD, and some cases of sporadic PD.¹ Hallmark signs and symptoms of PD (Figure 1.) are typically motor-related, for instance, the most common PD motor symptoms include bradykinesia, rigidity, resting tremor, stooped posture/unstable balance.^1,2

Figure 1. Hallmark Symptoms and Signs of PD.²

        The basal ganglia system plays a major role in the initiation of movements (motor planning) and muscle tone. Two of the major nuclei found in the basal ganglia are the substantia nigra and the striatum. The striatum is further divided into three subsections, the caudate nucleus, putamen, and nucleus accumbens. Together, the caudate nucleus and putamen form the dorsal striatum. The caudate nucleus receives afferent signals from the prefrontal cortex, and it is responsible for cognitive function and regulating eye movements. On the other hand, the putamen receives afferent inputs from the motor cortex and the substantia nigra and it controls motor function, specifically voluntary movement. Another key nucleus of the basal ganglia system is the substantia nigra. Neurons of the substantia nigra use dopamine as a neurotransmitter, giving this area its unique distinguishing appearance.

        The substantia nigra appears unusually dark even in the absence of stain; this distinctive characteristic is a result of neuromelanin. Neuromelanin is a dark pigment formed during dopamine metabolism and is continuously produced by the densely packed dopamine neurons of the substantia nigra. These dopaminergic neurons are projected from the substantia nigra to the putamen region of the striatum, these afferent fibers are known as nigrostriatal fibers.

        Parkinson’s Disease progressively affects the nervous system, slowly degenerating and destroying dopaminergic neurons in the substantia nigra. As PD advances fewer neurons can be found in the substantia nigra which means that less dopamine is being released into the striatum. The neurodegenerative effects and dysfunction of the nigrostriatal striatal system observed in PD patients are direct consequences of the striatal dopamine-deficiency. ^4,5 The absence of striatal dopamine results in the inability to conduct controlled, fine muscle movements.     

         Since there is no definitive diagnostic or imaging test to diagnose PD, diagnosis is made clinically. A clinical diagnosis of PD is only possible once the patient starts to exhibit symptoms of the disease. Once symptoms begin to manifest this indicates that the disease has progressed to a point where over 60% of nigral nerve cells have disappeared. ¹ Every case of PD progresses differently, the disease may differ in severity, rate of progression, and an individual may experience different PD symptoms, presentation of neuropathology, age of onset, etc. An example of the average or general progression of PD and the clinical symptoms associated with each stage is shown in Figure 2.

Figure 2. Clinical symptoms associated with PD and general disease progression.³

In many cases, after the patient succumbs to the disease their brain can be examined for conclusive evidence of PD. For example, by immunohistochemically staining the substantia nigra of a PD patient, researchers can establish the extent of neuronal degeneration by comparing the section to the immunohistochemically stained substantia nigra from a healthy patient. ^4,5

Unlike the healthy substantia nigra which consists of distinct deeply stained regions, a PD patient’s substantia nigra will show much lighter regions, ultimately allowing researchers to define the disease due to the observed depigmentation (Figure 3).³ 

Figure 3. Main neuropathologies observed in immunohistochemical stains of PD patients.³ 

In addition to the above-mentioned depigmentation neuropathological hallmark of Parkinson’s Disease is the presence of Lewy Bodies. Lewy Bodies are intracytoplasmic inclusions containing aggregations of the α‑synuclein protein.^1,3 Lewy Bodies are known to cause mitochondrial dysfunction by disrupting the electron transport chain which leads to the degradation of dopaminergic neurons in adulthood. Damage to the mitochondria causes diminished ATP levels in PD patients because of their impaired cerebral glucose metabolism and mitochondrial biogenesis. Cellular dysfunctions, including diminished ATP levels and impaired bioenergetics, have been regularly observed in PD patients and may determine the severity and course of the disease.⁶ As PD progresses, the abnormal deposition and aggregation of the α‑synuclein protein within cytoplasm gradually increase and begin to involve more brain regions.⁷ Shown in Figure 4 are examples of immunohistochemical staining of three unique Lewy bodies all differing in their morphological characteristics.

Figure 4. Immunohistochemical staining of α -synuclein shows characteristic Lewy bodies.³

    The gold standard for Parkinson’s Disease drug therapy is L-DOPA, also called levodopa. Systemic administration of L-DOPA in PD patients acts to pharmacologically substitute the diminished levels of dopamine in the striatum.¹ L-DOPA is the precursor to dopamine in the dopamine synthesis pathway, and unlike dopamine, can cross the blood-brain barrier.^1,8,9 While L-DOPA has been critical in reducing the motor dysfunction experienced by patients with PD, this revolutionary breakthrough treatment has been around for over 50 years without being improved or replaced. ^8,9

         L-DOPA treatment solely targets the negative consequences of PD on motor function, but it fails to prevent or slow down the degeneration of dopaminergic neurons. Even more alarming is that all current therapies for PD (including L-DOPA) are only focused on regulating and relieving the symptoms, while the underlying, causative neuronal degeneration remain ignored and thus progressive deterioration of the patients’ health still occurs.¹ However, a new pharmacologic breakthrough in the treatment of Parkinson’s may be on the horizon.

  This potentially revolutionary therapy for Parkinson’s treatment is not a novel drug, but instead is a “repurposed drug” called of terazosin. Terazosin is normally utilized for treating benign prostatic hyperplasia which is the enlargement of the prostate.¹⁰ Terazosin binds to and activates PGK-1 (phosphoglycerate kinase-1), which is the first ATP-producing enzyme in the glycolysis cycle.¹¹ The PGK-1 enzyme is one of only two enzymes in the glycolysis pathway that are capable of generating ATP.¹¹ Terazosin’s interaction with PGK-1 acts to intensify and strengthen the enzyme’s activity resulting in an upsurge of ATP.¹¹

  The application of terazosin for treating PD has been shown using a model of PD that is induced by MPTP. MPTP is a toxin that induces PD symptoms by destroying dopaminergic neurons, inhibiting the ETC in mitochondria, and lowering tyrosine hydroxylase levels (rate-limiting step in dopamine synthesis). Terazosin has proven effective in decreasing neurodegeneration, slightly reestablishing TH and dopamine, as well as, improving motor function all caused by MPTP.

Figure 5. Immunostaining of Striatum. 

Figure 5 illustrates the deep pigmentation characteristic to the striatum which under normal conditions is densely concentrated with neurons. The middle panels representing the striatum when exposed to MPTP in the absence of Terazosin shows a dramatic loss in pigmentation and therefore a loss in neuronal concentration within the striatum. The final two panels show the striatum exposed to MPTP and Terazosin. Due to the presence of Terazosin when MPTP is in the striatum, the neuronal concentration did not significantly deteriorate.¹⁰

            Terazosin appears to be an extremely effective treatment for PD; it has the potential to revolutionize the treatment of neurodegenerative diseases. Administering Terazosin, even after the onset of neurodegeneration, has been shown to successfully slow the rate of cell death, as well as, increase tyrosine hydroxylase levels, dopamine content, and motor performance.¹⁰

A major benefit of using a drug that is already well established and used clinically to treat other diseases is that the researchers were able to assess the efficacy of Terazosin in humans more easily and effectively. Additionally, they could easily distinguish and test for a Terazosin-induced effect due to the availability of a vast number of human clinical databases.¹⁰ Since Terazosin is not a ‘novel’ drug and has been regularly prescribed to many patients, its safety profile is well-documented. However, the researchers’ database analysis was limited to men since Terazosin is typically only prescribed for treatment of benign prostatic hyperplasia, a disease only affecting men. Another potential limitation of Terazosin is the fact that the exact mechanism that Terazosin employs to effect neurons remains unspecified. A final drawback of Terazosin is its tendency to reduce blood pressure, which is a cause for concern in PD patients who may already have low blood pressure.¹²

The exciting results obtained from the Terazosin study prove that Terazosin has the capability to effectively increase pyruvate levels (a glycolysis product) in the substantia nigra, striatum, and cerebral cortex. The resulting elevation in ATP levels (cellular energy) can alleviate cellular strain to meet energy demands and improve all aspects of neuronal function. Impaired energy metabolism is a common characteristic of PD as well as other neurodegenerative conditions like Alzheimer’s Disease. Therefore, the cellular benefits of Terazosin demonstrate that this drug can be used as a potential treatment for countless other neurodegenerative diseases. These promising results predict Terazosin to be a dominant candidate for clinical trials in PD, with the hope of repurposing this prostate drug to treat this widely prevalent and detrimental disease.

By Niamh Costello, Master's of Medical Science Student at the University of Kentucky 

 References

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2.      Oppenheimer, M. (2018, February 9). New Developments in Parkinson's Disease - TPG, Inc. http://www.tpgonlinedaily.com/new-developments-parkinsons-disease/.

3.      Poewe, W., Seppi, K., & Tanner, C. (2017). Parkinson Disease. Nature Reviews Disease Primers, 3(17013). doi: doi:10.1038/nrdp.2017.13

4.      Dickson, D., Braak, H., Duda, J., Duyckaerts, C., Gasser, T., Halliday, G., . . . Litvan, I. (2009). Neuropathological assessment of Parkinson's disease: Refining the diagnostic criteria. The Lancet Neurology, 8(12), 1150-1157.

5.      Halliday, G., Holton, M., Revesz, J., & Dickson, L. (2011). Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathologica, 122(2), 187-204.

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7.      Braak, Heiko, Tredici, Kelly Del, Rüb, Udo, De Vos, Rob A.I, Jansen Steur, Ernst N.H, & Braak, Eva. (2003). Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiology of Aging,24(2), 197-211.

8.      PD Med Collaborative Group. (2014). Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): A large, open-label, pragmatic randomized trial. The Lancet, 384(9949), 1196-1205.

9.      LeWitt, P. A., & Fahn, S. (2016). Levodopa therapy for Parkinson disease: A look backward and forward. Neurology, 86(14_Supplement_1 Suppl 1), S3-S12.

10.  Cai, R., Welsh, M., Liu, L., et al. (2019). Enhancing Glycolysis Attenuates Parkinson’s Disease Progression in Models and Clinical Databases. The Journal of Clinical Investigation. 129(10):4539-4549. https://doi.org/10.1172/JCI129987

11.  Xinping Chen, Chunyue Zhao, Xiaolong Li, Tao Wang, Yizhou Li, Cheng Cao, . . . Lei Liu. (2014). Terazosin activates Pgk1 and Hsp90 to promote stress resistance. Nature Chemical Biology, 11(1), 19-25.

12.  Shugart, J. (2019, September 20). In Mice and Men, Prostate Drug Reportedly Treats Parkinson's Disease. https://www.alzforum.org/news/research-news/mice-and-men-prostate-drug-reportedly-treats-parkinsons-disease.