Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by symptoms that include bradykinesia, gait instability, rigidity, and resting tremor (Jankovic, 2008). PD is one of the most common neurodegenerative disorders and motor symptoms seem primarily due to the loss of dopamine (DA) along the nigrostriatal pathway. The loss of DA results in the alterations of DA-stimulated motor function (Meshul et al., 1999; Touchon et al., 2004; Holmer et al., 2005a, Holmer et al., 2005b; Smith et al., 2011) and has been shown to alter striatal glutamate levels (Klockgether et al., 1991; Meshul et al., 1999; Robinson et al., 2003; Walker et al., 2009), which in time results in an imbalance of overall DA and glutamate neurotransmission. Morphologically, we have reported changes in striatal glutamate synapses following a lesion of the DA nigrostriatal pathway, suggesting the importance of the interaction between DA and glutamate (Meshul et al., 1999; Meshul et al., 2000; Robinson et al., 2001, Robinson et al., 2003; Holmer et al., 2005a, Holmer et al., 2005b). There is no treatment that has conclusively been shown to slow or restore the loss of nigrostriatal DA. The current gold standard of treatment, levodopa (L-dopa), results in symptomatic relief of the motor dysfunction, but over time, there is continued loss of nigrostriatal DA and this DA replacement therapy becomes less efficacious. Therefore, treatment strategies that alter the underlying pathology are needed to slow progression of the disease. In addition, better translational animal models are needed to test restorative capabilities of these treatments. We argue that a prophylactic, neuroprotective study design in an acute or chronic animal model of PD will not be as translational as starting the treatment following the chronic/progressive loss of nigrostriatal DA, as is seen in real world patients already diagnosed with PD. This restorative/recovery treatment protocol at this time is essential since patients will be diagnosed with PD only after motor symptoms are apparent. Within the first 3–5 years after diagnosis, it has been reported that there is already substantial loss (∼60–80 %) of nigrostriatal DA neurons in the substantia nigra pars compacta (SNpc) and in terminals in the putamen in these early identified PD patients (Kordower et al., 2013). This is an important point in terms of starting treatment in an animal model of PD after there is already a significant lesion of the nigrostriatal pathway. We have previously shown the translational potential of our progressive mouse model of PD where intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over 4 weeks of time (5 days/weeks), with increasing doses each week, results in an escalating loss of tyrosine hydroxylase (TH) within the dorsolateral (DL) striatum and substantia nigra (SN) over time and the appearance of motor deficits (Goldberg et al., 2011a, Goldberg et al., 2011b, Goldberg et al., 2012; Sconce et al., 2015b; Churchill et al., 2017, Churchill et al., 2019; Massaquoi et al., 2020).

Since all clinical trials have been unsuccessful at significantly slowing the progression of PD (i.e., disease modification) and L-dopa is used only to ameliorate the symptoms, other strategies must be considered. The treatment of PD using natural products is now of growing interest. There have been a handful of clinical trials that have evaluated Mucuna pruriens as a comparison to standard levodopa-carbidopa therapy in people with PD (HP-200 in Parkinson's Disease Study Group, 1995; Katzenschlager et al., 2004; Cilia et al., 2017, Cilia et al., 2018). However, these studies are limited by small sample size (range n = 8 to n = 18) and short intervention times (1 day to 16 weeks) (HP-200 in Parkinson's Disease Study Group, 1995; Katzenschlager et al., 2004; Cilia et al., 2017, Cilia et al., 2018). There are two case studies of patients reporting longer-term use of Mucuna pruriens. Radder et al. report a 48-year-old woman with PD who had been using Mucuna pruriens for several years without a decarboxylase inhibitor with benefit but when motor symptoms started to progress, a decarboxylase inhibitor was added with significant improvement in motor symptoms, including gait (Radder et al., 2019). Margolesky et al. report a 71-year-old man whose PD motor symptoms started when he was 53 years, who could not tolerate standard levodopa-carbidopa therapy and used Mucuna pruriens without a decarboxylase inhibitor for at least 10 years for motor symptoms until he developed motor fluctuations (shorter ON times) and levodopa-related dyskinesia (Margolesky et al., 2020). It is unclear from the two case reports of longer-term use of Mucuna pruriens whether non-L-dopa plant constituents are involved in improving motor symptoms or if this is a mainly an L-dopa phenomenon. The Margolesky case report hints at a non-L-dopa mechanism as the patient did not use a decarboxylase inhibitor. If Mucuna pruriens contains non-L-dopa constituents that can improve motor symptoms, then further evaluation is warranted.

In pre-clinical in vitro and in vivo studies, Mucuna pruriens may be neuroprotective, as it functions as an antioxidant and protects against oxidative damage (Rai et al., 2017; Johnson et al., 2018). However, preventative treatment with Mucuna pruriens did not block the loss of tyrosine hydroxylase (TH) within the striatum following acute MPTP administration (Kasture et al., 2009). This finding may depend on the method of Mucuna pruriens extraction and the animal model being investigated, which are both different compared to the current stud. A unique feature of Mucuna pruriens is that it contains among the highest levels of L-dopa in plants (Ramya and Thaakur, 2007). Although the presence of L-dopa in Mucuna pruriens may be important in terms of treating the symptoms of patients with PD, it is most likely that the other ingredients in Mucuna pruriens will play a major role in terms of neurorestoration because L-dopa itself is not known to have this property, although the debate regarding this issue continues (Rato et al., 2019). We have found that using a neuroprotective study design, administration first of a progressive dose of MPTP (Massaquoi et al., 2020; Moore et al., 2021), then followed immediately by treatment with L-dopa (15 mg/kg/d, IP)/benserazide (12 mg/kg/d, IP) in mice, did not prevent/block the MPTP-induced loss of TH positive terminals in the striatum or TH positive neurons in the SNpc (Meshul, Winfrey, Moore, unpublished findings). It is uncertain at this time as to whether treating PD patients with Mucuna pruriens actually slows the progression of the disease, outside of treating the symptoms. Therefore, the goal of this pre-clinical study was to determine if daily oral treatment with an extract of Mucuna pruriens, following the loss of nigrostriatal dopamine using chronic/progressive MPTP administration, would result in recovery/restoration of both motor function and in TH protein expression in the nigrostriatal pathway.