Parkinson's disease (PD), also known as paralysis agitans, is a progressive neurodegenerative disease that commonly affects middle-aged and older people. Currently, neurological diseases are the leading cause of disability worldwide, and the incidence of PD is increasing rapidly. PD seriously affects quality of life and represents a great burden on patients, their families, and society as a whole. Epidemiological surveys show that PD is the second most common neurodegenerative disease after Alzheimer's disease.[5,6] Therefore, PD has become a significant medical and social concern.
PD typically develops in middle-age, with occult early onset and slow progression. The characteristic symptoms of PD are tremor, muscle rigidity, slow movements, and postural instability. Pathological changes in this disease include the degeneration and loss of dopaminergic neurons in the nigrostriatal region and the formation of Lewy bodies. Patients develop a series of clinical symptoms caused by this decrease in dopamine neurotransmitters. The pathogenesis of PD is complex and diverse, and include environmental and genetic factors, mitochondrial dysfunction, oxidative stress, and inflammatory responses. Several genes have been reported to be associated with PD, including PARKIN (also known as PARK2), PINK1 (also known as PARK6), DJ-1 (also known as PARK7), VPS35, LRRK2 (also known as PARK8), ATPl3A2 (also known as PARK9), UCHL1 (also known as PARK5), GBA1, and SNCA (also known as PARK4, this encodes the α-synuclein protein).
Mutations in PARKIN, PINKl, DJ-1, and VPS35 impair mitochondrial function and affect neuronal activity.LRRK2 regulates mitochondrial function, autophagy, and neuroinflammation, and mutations in this gene can cause the degeneration of dopaminergic neurons. Mutations in ATP13A2 affect cellular oxygen consumption and mitochondrial membrane potential while GBA1 mutations increase the likelihood of developing GBA1-related PD. Mutations in SNCA result in the abnormal expression of α-synuclein, which aggregates in neurons, forming Lewy bodies. Released α-synuclein activates microglia and induces the increased production of reactive oxygen species (ROS) and inflammatory mediators such as interleukin 13 and tumor necrosis factor α, which promote inflammatory responses and exacerbate degenerative lesions in dopaminergic neurons. Increased neuronal concentrations of α-synuclein can induce metabolic disorders, lipid peroxidation, protein and DNA damage, and eventually the degeneration of dopaminergic neurons. Thus, the protection of mitochondrial function, reduction of oxidative stress, and inhibition of inflammatory responses are critical components of new strategies for the treatment of PD. Currently, the main treatments for PD include surgery, rehabilitation, acupuncture, and nursing; however, the most commonly used treatments are drug therapies (Fig. 1).
The main therapeutic drugs include compound levodopa, dopamine receptor agonists, monoamine oxidase-B inhibitors, catechol oxymethyltransferase inhibitors, and other ancillary drugs; however, all of these drugs cause significant adverse reactions. Therefore, the identification and development of new drugs for the treatment of PD is urgently required.
Metformin is the first-line treatment for type 2 diabetes according to many guidelines. Its main pharmacological action is to inhibit hepatic glucose output, to improve the sensitivity of peripheral tissues to insulin, and increase the uptake and use of glucose to lower blood sugar levels. Metformin exerts multi-faceted regulatory functions by activating the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. In addition to treating type 2 diabetes, metformin is also effective against other diseases. In the cardiovascular system, the drug can inhibit the formation of atherosclerosis, regulate blood pressure and blood lipids, and control body weight.[21–23] Metformin application has also been reported in conditions such as pre-eclampsia and congestive heart failure.[24,25] Furthermore, in the female reproductive system, the drug has clinical efficacy in the treatment of polycystic ovary syndrome and gestational diabetes, as well as in the adjuvant treatment of breast cancer, ovarian cancer, endometrial cancer, and a variety of other female reproductive system tumors.[26–28] In addition, metformin is potentially effective in the treatment of nonalcoholic steatohepatitis, tubulointerstitial fibrosis, and multiple sclerosis.[29–31] Metformin also plays a positive role in neuroprotection by mediating the inhibition of inflammatory responses, improving cognitive impairment, and treating some forms of autism. These results highlight its potential application in the treatment of PD.[32–35]
Database search strategy
The authors included studies that discussed the potential role of metformin in the treatment of PD. English language and full-text articles published between 2002 and 2019 were included in this non-systematic review. The authors searched the PubMed database to identify relevant publications. Publications were chosen that specifically discussed inducing plasticity with the following terms: metformin, PD, type 2 diabetes, neuroprotective effects, and AMPK. The results were further screened by title and abstract for comorbidity of PD and diabetes, the neuroprotective effects of metformin, or metformin treatment of PD. The data extraction process focused on the neural effects of metformin and the potential role of metformin in the treatment of PD.
Comorbidity of Parkinson's disease and diabetes
Both PD and diabetes are associated with environmental factors and have genetic susceptibility.[36–38] The incidence of both chronic diseases is age-related, and they are both associated with similar metabolic disorders and pathogenic pathways.[39–41] There is increasing evidence that PD susceptibility is increased in patients with type 2 diabetes, and PD patients often have co-existing insulin resistance. As shown in Figure 2, there is a significant link between PD and the pathogenesis of diabetes according to the aforementioned relevant publications.
PD has similar risk factors and genetic susceptibility to diabetes
It has been proposed that environmental factors such as metal ions, including iron and zinc, are important risk factors for PD and Alzheimer's disease; diabetes risk is also increased by exposure to heavy metals such as zinc, manganese, cadmium which affects glucose homeostasis. In terms of genetic susceptibility, α-glucosidase is an important factor affecting peripheral blood glucose fluctuations in patients with type 2 diabetes, and mutations in the glucosidase gene in the brain are closely related to neurological dysfunction in PD patients. PD can also be caused by mutations in DJ-1, which regulates astrocyte hyperplasia by activating the signal transduction and activator of transcription-3 pathway; DJ-1 expression is reduced in the islet cells of type 2 diabetic patients. This evidence suggests a molecular basis for the comorbidity of PD and diabetes.
PD has a similar pathogenesis to diabetes
An epidemiological investigation into insulin resistance revealed a significant increase in body weight in PD patients after diagnosis. In PD patients with dementia, 30% had impaired glucose tolerance, 5.6% were diagnosed with diabetes, and 26% had insulin resistance only. In addition, a phenomenon similar to the process of peripheral insulin resistance occurs in the brain of PD patients, suggesting that the insulin resistance may be an important factor in PD pathogenesis. It has been shown that increased ferritin and impaired glucose homeostasis might increase the risk of diabetes, and these ions are known to generate large amounts of free radicals via the Fenton reaction, thus causing the degeneration of dopaminergic neurons. Therefore, iron metabolism might be a common factor related to both diabetes and PD. Insulin receptors are also present in the basal ganglia and substantia nigra, and insulin plays an important role in neuronal survival, growth, and regeneration, as well as in neurotrophy, neuromodulation, and synapse maintenance.[54–56] Dopaminergic neuron degeneration is the most important pathological change in PD, and insulin resistance in the brain can induce the dysfunction of mitochondria and dopaminergic neurons. Pyramidal neurons in the cerebral cortex, hippocampus, and olfactory bulb produce insulin-like growth factors (IGFs), and downregulation of IGF-1 signaling can lead to cognitive impairment in vascular dementia. Therefore, IGF-1 deficiency may be associated with the development and progression of neurodegenerative diseases. In addition, protein kinase B (also known as Akt), which is an important downstream target of the insulin signaling pathway, is also closely related to PD. Akt associates with mammalian target of rapamycin (mTOR) to form the Akt-mTOR axis, which is considered central to the insulin signaling cascade. In addition, the Akt signaling pathway plays a central role in insulin-stimulated glucose metabolism and cell survival. AMPK is a key regulator of mitochondrial synthesis but it is also a neuroprotective factor. AMPK expression is decreased in patients with insulin resistance, which leads to impaired mitochondrial function, damaged cell structures, and ultimately, the death of dopaminergic neurons. Thus, improving insulin resistance may be a potential therapeutic target in the treatment of neurodegenerative diseases.
Under conditions of cellular oxidative–reductive (redox) imbalance, oxidative stress damages cell membranes and other biomolecules, and is associated with a variety of neurological diseases.[64–66] Dopamine is highly susceptible to oxidation, a reaction that is thought to be the main cause of PD by directly causing neuronal damage and progressive degeneration of dopaminergic neurons in the nigrostriatal region of the brain. Studies have shown that ROS influence glucose metabolism by upregulating the pentose pathway, thereby inducing insulin resistance in patients with type 2 diabetes. The production of reactive oxygen species (ROS) leads to oxidative stress, causing the death of dopaminergic neurons and the partial discharge of their cell contents. One cause of oxidative stress is the upregulation of nitric oxide synthase (NOS), which exists in 3 forms: inducible NOS, endothelial NOS, and neuronal NOS (nNOS). single nucleotide polymorphisms in NOS1 can modify NO production in neurons and may be associated with neurological diseases. DNA damage is a proposed pathogenic factor for PD, and a previous study showed that both cyclooxygenase-2 and nNOS interact with oxidative stress to cause DNA damage in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. All of these factors suggest that NOS may induce oxidative stress, thus causing cognitive impairment in PD patients. Factors involved in the molecular mechanisms of oxidative stress include changes in DJ-1 expression, mitochondrial dysfunction, and excitatory toxicity of N-methyl-D-aspartate receptors induced by glutamate overstimulation. N-methyl-D-aspartate receptor overstimulation causes extracellular Ca2+ influx, resulting in nNOS activation. Activated nNOS produces nitric oxide and reacts with other ROS to form highly toxic peroxynitrites, which cause protein nitrification, lipid peroxidation, and DNA fragmentation to induce cellular damage. Therefore, oxidative stress is likely to be a common factor in the pathogenesis of both insulin resistance in type 2 diabetes and dopaminergic neuronal damage in PD.
Inflammation is also associated with the onset of type 2 diabetes and insulin resistance. Furthermore, inflammation has also been identified as a major risk factor for PD, both genetically and because the secretion of high levels of pro-inflammatory mediators from chronic microglia activation cause neuronal damage and promote neurodegeneration. Therefore, anti-inflammatory immunomodulatory therapy may become an important approach for the prevention and control of PD and its complications.
Type 2 diabetes increases PD risk
Multiple epidemiological cohort studies have revealed a significant increase in PD risk in patients with type 2 diabetes. Both PD and diabetes have a high prevalence in the older population. PD patients with diabetes show increased dopamine release compared with PD patients without diabetes. The simultaneous presence of diabetes in patients with PD may accelerate the deposition of amyloid plaques in the brain or exacerbate brain atrophy, causing severe cognitive impairment in PD patients.[84,85] Other studies have indicated that the presence of diabetes leads to more severe cognitive dysfunction, postural instability, and gait difficulty via mechanisms other than the nigrostriatal dopaminergic neuron degeneration that typically occurs in patients with PD[86,87]; however, the specific mechanism remains to be clarified. In addition, diabetes may be associated with more severe motor impairment in PD. Although the mechanisms of PD are complex, the association between type 2 diabetes and PD may provide a new direction for the development of therapeutic strategies in PD.
Neuroprotective effects of metformin
Insulin is a polypeptide secreted by islet β cells. In addition to its unique hypoglycemic function, the role of insulin in the nervous system is attracting increasing attention. Insulin contributes to the development and repair of nerves by signaling via the tyrosine kinase receptor pathways. Insulin signaling in the nucleus alters the expression of axon-related proteins and drives the regeneration of distal axons. In a rat model of insulin-deficient type 1 diabetes, the sustained delivery of exogenous insulin restored the normal function of damaged nerves and protected the central nervous system from damage. Additionally, retinal neuron regeneration in type 1 diabetes patients can be promoted by treatment with insulin eye drops or intravenous infusion, and the use of insulin and metformin to treat patients with gestational diabetes can effectively control blood glucose levels and reduce the incidence of abnormal neurodevelopment in neonates. Thus, there is substantial evidence that insulin metabolism can influence the development, regulation, and repair of the nervous system.
Diabetes comprises a group of metabolic diseases characterized by hyperglycemia, mainly caused by impaired insulin secretion or its biological effects, or both. This condition causes chronic damage and dysfunction in various tissues due to long-term hyperglycemia. Diabetic peripheral neuropathy and diabetic encephalopathy are important complications in the nervous system in this disease, suggesting that the drugs used to treat diabetes may also have an impact on neurological diseases.[93,94]
Metformin is a hypoglycemic drug that improves insulin resistance and regulates insulin metabolism, and which is advantageous because it has few side effects and is cheap to purchase. Early studies showed that metformin not only reduces blood sugar levels, but also directly inhibits the formation of advanced glycation end-products, thus effectively preventing diabetes complications. Subsequent studies showed that metformin promotes nerve regeneration after diabetic sciatic nerve injury, thus reflecting its therapeutic value for the repair of diabetic peripheral nerve injury. Recently, autophagy was identified as an intracellular catabolic process with neuroprotective properties. One study reported that metformin enhances autophagy by inhibiting apoptosis and inflammation via the mammalian target of the rapamycin (mTOR)/p70S6 kinase (p70S6K) signaling pathway, thereby exerting neuroprotective effects in spinal cord injury in rats. Metformin can also effectively improve the glucose uptake function of insulin-resistant neuronal cells by activating AMPK, insulin receptor β subunit (IRβ), insulin receptor substrate 1, and phosphatidylinositol 3 kinase. Furthermore, metformin has been shown to exert neuroprotective effects against primary neuronal apoptosis. It can also reduce subgranulocyte proliferation and normalize neuroblast differentiation in the hippocampal dentate gyrus in a diabetic rat model. In a rat model of anxiety established using methamphetamine, metformin exerted antioxidant effects and upregulated antioxidant enzymes (such as superoxide dismutase and glutathione), suggesting that metformin reduces methamphetamine-induced neurodegenerative changes via the cyclic adenosine monophosphate response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) or Akt/glycogen synthase kinase-3 pathways. One study also reported that metformin improves cognitive impairment and reduces oxidative stress in the brains of mice with generalized convulsive seizures induced by acute pentylenetetrazole. Chronic L-methionine administration causes hyperhomocysteinemia and impaired memory, and a previous study in rats reported that metformin may restore L-methionine-induced memory impairment by normalizing oxidative stress levels in the hippocampus. Metabolic memory, which refers to persistent diabetic stress even after the normalization of blood glucose, is a major cause of diabetic complications. A glucagon-like peptide-1 receptor agonist can alleviate neuronal damage and reduce neuronal metabolic memory in animal models of diabetes-related dementia. Glucagon-like peptide-1 receptor agonist treatment also promotes neuronal growth and repair and reduces inflammation, apoptosis, and oxidative stress, and treatment with glucagon-like peptide-1 analogs and metformin improves cognitive impairment. The long-term consumption of a high-fat diet (HFD) in rat models causes insulin resistance, and a HFD consumption also causes brain mitochondrial dysfunction and cognitive impairment. Metformin could completely restore brain mitochondrial function in these long-term HFD rat models, and also restored the learning and memory behaviors that were impaired by long-term HFD consumption. Damage caused by factors such as increased oxidative stress, blood–brain barrier disruption, inflammation, and mitochondrial dysregulation, may result in neuronal death. A recently review shows that metformin may improve functional recovery via these mechanisms following experimental cerebral ischemia/reperfusion injury. Furthermore, metformin activates an atypical protein kinase C–CREB-binding protein pathway, promotes neurogenesis and spatial memory formation, and effectively improves memory impairment in type 2 diabetic male db/db mice with hyperinsulinemia. A recent study also reported that saffron and metformin combination therapy improves learning and memory disorders in streptozotocin-induced diabetic rats via a mechanism that may involve the inhibition of oxidation, inflammation, and apoptosis, among other processes. In addition to its neuroprotective effects in diabetic patients, studies have also indicated a protective function against experimental acrylamide-induced neurological disease in rats via its effects in restoring lipid peroxidation in the brain and spinal cord, reducing caspase-3 protease activity, and upregulating Bcl-2 expression in the brain and sciatic nerve. Painful diabetic neuropathy is a common complication in patients with diabetes, often causing severe hyperalgesia and analgesia. In a study of hyperalgesia and analgesia pain-induced diabetic neuropathy in a streptozotocin-induced diabetic rat model, metformin was shown to activate the AMPK pathway in the sciatic nerve by increasing AMPK expression and via the antioxidant effects of the AMPK signaling pathway, thus leading to the amelioration of painful diabetic neuropathy. However, metformin may cause vitamin deficiency in the treatment of type 2 diabetes; therefore, to avoid exacerbating neurological damage with depression or cognitive decline, it may be necessary to screen for cobalamin deficiency in patients with diabetes who are taking metformin. Overall, metformin promotes autophagy, has anti-inflammatory, antioxidative, and anti-apoptotic effects on the nervous system, and exerts neuroprotective effects through activation of the AMPK, caspase-3, Bcl-2, mTOR/p70S6K, CREB/BDNF, and Akt/glycogen synthase kinase-3 signaling pathways (Table 1).
Metformin treatment of Parkinson's disease
Studies have shown that anti-diabetic drugs promote neuronal survival, affect brain metabolism and nerve inflammation and regeneration, and lead to improved memory and cognition. Therefore, antidiabetic drugs are potential therapeutic agents for the treatment of neurological diseases. Metformin is a first-line hypoglycemic agent for the treatment of insulin-resistant (type 2) diabetes mellitus. The role of metformin in cell metabolism, neuronal protection, and improvement of cognitive impairment suggests that metformin may alleviate, or even cure, PD-related symptoms (Fig. 3).
Metformin increases neurogenesis and spatial memory formation and reduces the risk of PD. Metformin also prevents haloperidol-induced hydrogen peroxide formation by inhibiting oxidation/nitrification stress, suggesting an adjuvant role in the treatment of PD. Furthermore, metformin has neuroprotective effects in the MPTP mouse model of PD, with long-term metformin treatment resulting in significantly improved movement and muscle activity compared with the effects of short-term treatment. Furthermore, compared with the MPTP-negative control group, both the antioxidative activity of metformin and BDNF levels were significantly improved. Other studies have shown that metformin is neuroprotective against the neurotoxic effects of MPTP by inhibiting α-synuclein phosphorylation and increasing BDNF levels in the substantia nigra. These experiments in animal models provide preclinical support for the treatment of PD with metformin.
Metformin exerts its neuroprotective effects mainly by activating the AMPK–autophagy signaling pathway and inhibiting metabolic inflammation, which represents a therapeutic target in PD. The decreased activity of neural stem cells in older people is associated with the decreased expression of AMPK and mitochondria-associated genes/proteins (eg, peroxisome proliferator-activated receptor γ coactivator-1α, nuclear respiratory factor-1, mitochondrial transcription factor A (Tfam)) and the increased activity of caspase-3 and caspase-9. Metformin prevents the aging-induced release of cytochrome C from the mitochondria into the cytosol in human neural stem cells. Co-treatment with metformin abolishes the effects of aging on human high cervical myeloid cells and significantly reverses the decreased expression levels of senescence-related neuroprotective genes (PPARγ, Bcl-2, CREB). Results from these studies indicate the potential of the AMPK pathway as a therapeutic target for the treatment of diabetic neurodegeneration.
However, the long-term use of metformin slightly increases the risk of Alzheimer's disease and vascular dementia.[121,122] The decrease in BDNF suggests a potential state of vulnerability for the brain, as well as a decrease in neuroplasticity, which is necessary for enhanced cognitive effects. Long-term use of metformin reduces BDNF transcription and inhibits nuclear factor E2-related factor 2 (Nrf2), which may increase the vulnerability of the central nervous system. Some studies have also suggested that metformin increases the risk of PD or even aggravates neuronal damage. For example, metformin inhibited the MPTP-induced brain inflammatory response through iNOS, IL-1β, and TNF-α, affecting the microglia polarization state under conditions of neurodegeneration. However, MPTP and metformin may act in an additive manner to inhibit complex I of the electron transport chain in Parkinsonian patients, thus reducing ATP levels. Despite inflammatory parameters being decreased, a dose of MPTP lower than that of metformin may increase neuronal damage and exacerbate the vulnerability of neurons, which are particularly sensitive to the inhibition of complex I in the electron transport chain.
Therefore, the indications for the safe use of this drug therapy should be carefully controlled for patients requiring long-term and high-dose treatment with metformin.
By reviewing the occurrence, development, and biochemical changes of PD, as well as the possible mechanisms underlying the effects of metformin on various aspects of PD (especially in the nervous system), we have revealed the potential link between PD and metformin. This information provides a theoretical basis for the treatment of PD with metformin. Moreover, advances in the fields of epidemiology, animal models, and molecular biology have facilitated the accumulation of evidence to support the therapeutic potential of metformin in PD.
Metformin significantly improves insulin resistance in patients with PD, prevents further neuronal damage in PD patients with comorbid diabetes, and plays a role in neuroprotection and cognitive impairment. Metformin is associated with multiple signaling pathways, including the AMPK, caspase-3, Bcl-2, and mTOR/p70S6K pathways, which have anti-inflammatory, anti-oxidative, and anti-apoptotic effects, and promote autophagy, alleviate neuronal damage, reduce complications, and delay disease progression in PD patients. Therefore, the use of metformin for the treatment of PD has the potential for broad application.
Unfortunately, the pathogenesis of PD is still unclear, mainly because of its complexity. Although metformin has many advantages, certain problems and challenges remain in its clinical application for the treatment of PD.
In summary, current studies into the treatment of PD with metformin are mostly in the preclinical stage of animal experimentation. Most of these studies indicate the benefits of metformin in treating PD, but the use of metformin in clinical treatment remains to be verified.
We are indebted to all the individuals who participated in, or helped with, our work.
JM and ML designed the manuscript. HC, FN, XW, and ZT collected the data. ML and FN drew the figures. ML, HC and JM wrote the initial draft of the manuscript. All authors approved the final version of the manuscript.
This work was supported by the Natural Science Basic Research Plan in Shaanxi Province of China (No. 2019JM-098, to JM), the National Natural Science Foundation of China (No. 31371298, 81301151, to JM), Opening Project of the Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong University, China (No. 2017LHM-KFKT007, to JM), the National Innovation Experiment Program for University Students (No. GJ201810698126, to JM).
Conflicts of interest
The authors declare that they have no conflicts of interest.
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