Can stress cause neuropathy

Contents

Anxiety and Peripheral Neuropathy

Peripheral neuropathy literally translates as peripheral nerve pain.. It’s generally caused by something that damages the nerves directly, and leads to changes of functioning in some parts of the body that can cause symptoms that may be extremely distressing.

Many people with anxiety believe they have developed peripheral neuropathy, and some even believe that anxiety can cause it. But does anxiety cause peripheral neuropathy, and how can you reduce the sensations?

Types of Anxiety and Peripheral Neuropathy

Peripheral neuropathy has a lot of different types of symptoms. Some of the most common include:

  • Tingling or crawling sensations.
  • Numbness or trouble with movement.
  • Pins and needles (like when a limb falls asleep).

Cramping, pain, and heaviness may also occur. But each one depends on the location of the nerves, the type of damage, and so on.

Anxiety doesn’t actually create peripheral neuropathy. While anxiety and stress have been thrown around as possible issues that lead to neuropathy, peripheral neuropathy is about nerve damage, not nerve symptoms, and since anxiety is unlikely to cause nerve damage, it can’t technically be peripheral neuropathy.

But anxiety can cause symptoms that resemble this type of disorder. Anxiety very commonly causes tingling, numbness, burning, or movement issues in various areas of the body, and when it does it can be very scary. Those that selfdiagnose often come up with health reasons that cause these symptoms, but they may be caused by anxiety.

How Peripheral Neuropathy is Diagnosed

If you are concerned that your symptoms are the result of a physical medical issue rather than anxiety you may want to undergo some diagnostic tests that can be ordered by your doctor. These will test your nerve function and health which will be able to show if you have true organic disease or if your symptoms are the result of hyperventilation and stress.

Electromyography

This test uses two fine needles to send electricity through your muscles. Any change in the signal could mean that there is underlying disease affecting your nerves.

Biopsy

A small sample of your muscle is taken using a needle and looked at under a microscope in a lab. Different types of nerve cell damage can be seen if your symptoms are not the result of anxiety.

Scans

MRI and CT scans can show pressure points where nerves have been crushed by bone, usually around your spine. Treatment for this can range from physiotherapy to surgery and treatment of any anxiety will not cure the symptoms.

How Anxiety Causes Similar Symptoms

Anxiety causes several issues that may lead to the development of these types of symptoms. Just a small sample includes:

  • Hyperventilation Hyperventilation is very common when you have anxiety, and when you hyperventilate your blood vessels constrict which takes away blood flow from some parts of your body. Without blood flow, these areas start to tingle, burn, etc.
  • Nerve Firings There is some evidence that anxiety causes the nerves to fire more, which can also lead to this feeling as though your nerves are always activated and cause “nerve damage-like symptoms” that can be hard to deal with. Anxiety can also cause cramps and other issues that are related to nerves.
  • Over Awareness Another problem is the result of over-awareness. When you’re overly aware of your body, you can have trouble moving them leading to issues with gait (walking style) and how your body feels. It may feel heavier, or harder to move, etc. Over Awareness is a serious issue that can also make otherwise healthy issues (like your leg waking up after sitting in an uncomfortable position) worse.

All of these are very similar symptoms to what people experience when they have peripheral neuropathy, which is why it’s so easy to self-diagnose peripheral neuropathy when in reality you just have anxiety.

How to Overcome Neuropathy-Like Symptoms

Reducing these types of issues that can lead to peripheral neuropathy-like symptoms can be tough. Ideally you need to combat your anxiety altogether. But in the meantime, consider the following:

  • Breathe Better First and foremost, you need to breathe better. If you find yourself hyperventilating too often, make sure you slow your breathing down considerably. Take as long as 5 seconds to breathe in, hold for 2 seconds, and breathe out for 7. Slowing down your breathing is very important for controlling anxiety.
  • Distract Your Mind The other key is about distraction. Remember that many of the symptoms you have are related to thinking too much about how some parts of your body feel. Keep your mind busy as much as you can. You need to distract your mind from focusing too heavily on your body, because only by doing that can your body’s movements feel more natural again.

But of course, these are only the beginning, and aren’t going to cure your anxiety. These will simply decrease the severity of what you experience, so that hopefully you can reduce some of your peripheral neuropathy like symptoms.

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Questions to Ask Your Health Care Team About Neuropathy

  • What are the symptoms and treatment of neuropathy?
  • What treatments might work for me?
  • How do I manage the symptoms of neuropathy? Can I get physical and occupational therapy?
  • Is there a long-term survivor group for living with neuropathy?

Peripheral neuropathy may develop at any phase of the cancer journey, even some time after treatment is finished. Knowing what some of the causes are and being able to describe your symptoms to your health care team can help you manage neuropathy. Symptoms are often ignored by both patients and health care professionals. If you have symptoms of neuropathy, it is important to discuss this with your health care team as soon as possible.

Symptoms of Neuropathy

Peripheral neuropathy can affect the nerves that tell you the position of your hands or feet that let you sense hot or cold or that senses pain. You can experience a tingling or numbness in certain areas of the body, commonly the hands and feet. These sensations can range from mild to painful and are almost always greatest at night.

Common signs and symptoms include:

  • Numbness or tingling, especially of the hands or feet.
  • Pain or cramping, especially of the hands, feet or calf muscles.
  • Sensitivity to touch or temperature.
  • Loss of reflexes.
  • Muscle wasting in the hands and feet.
  • Weakness, especially in the feet or hands.
  • Clumsiness.
  • Loss of balance, particularly in the dark.
  • Dizziness, especially when getting up from a bed or a chair.
  • Sexual dysfunction.

It’s not easy to deal with neuropathy. If you notice symptoms, talk to your health care team immediately.

Factors that Increase Risk of Neuropathy

Neuropathy may occur from cancer or the treatment received. Cancer types with higher risk of neuropathy include: lung, breast, ovarian, myeloma, lymphoma and Hodgkin’s disease and testicular.

Life factors that may increase the chances of developing neuropathy:

  • Advanced age.
  • A family history of neuropathy (such as with familial diabetes).
  • Malnourishment.
  • Excessive use of alcohol.
  • Having a preexisting medical condition such as diabetes or thyroid dysfunction.
  • Some medications (including chemotherapy medications) also increase risk.

Medications that may increase the risk of neuropathy:

  • Platinum compounds.
  • Taxanes.
  • Vinca alkaloids.
  • Thalidomide.
  • Velcade.
  • Cytosine arabinoside.
  • Misonidazole.
  • Interferon.

Discuss all of these risks with your health care team.

Treatments for Neuropathy

The peripheral nerves have a great ability to heal. Even though it may take months, recovery can occur. However, in some situations, symptoms of neuropathy may lessen but not completely go away. For example, nerve injury caused by radiation often does not recover well. Neuropathy caused by chemotherapy is also difficult to cure, and recovery may take 18 months to five years or longer. During recovery of platinum-induced neuropathy, patients may suffer increased symptoms.

Treatments for peripheral neuropathy depend on the cause. For instance:

  • If it is related to nutritional deficiencies, supplements may help.
  • If the neuropathy is related to a medical condition, such as diabetes or thyroid dysfunction, treating the condition can sometimes reverse the neuropathic symptoms.
  • For neuropathy related to chemotherapy, most treatments are supportive and designed to improve symptoms and function.
  • If problems develop during treatment and you continue to receive chemotherapy, the neuropathy can get worse.
  • Clinical trials research shows promise in some treatments with medications that help peripheral nerves to heal and prevent the neuropathy associated with chemotherapy from occurring or being as severe.

Recovery may be helped by:

  • Good nutrition including foods rich in thiamine, protein and antioxidants.
  • Controlling and correcting contributing conditions such as diabetes or hypothyroidism.
  • Appropriate pain medications.
  • Physical and occupational therapy.

How Neuropathy Affects Your Life

Pain from neuropathy can greatly affect your daily activities and quality of life. Symptoms of neuropathy can range from mild to severe. Each survivor’s experience will be different. However, with appropriate treatment, the effects of neuropathy can be limited.

If you have neuropathy, you may have:

  • Difficulty standing for long periods or walking without assistance.
  • Problems with balance and an increased risk of falling.
  • Difficulty with activities like buttoning and tying laces or ties.
  • Sensitivity to heat or cold.
  • Numbness or lack of pain sensation.
  • Pain.

Survivors with temperature sensitivity should avoid extreme temperatures, and use protective clothing as needed. If there is numbness or an inability to feel pain, it is important to pay careful attention to the skin on the hands and feet because there could be an undetected wound or a break in the skin.

Find a Neuropathy Support Group

  • Ask your health care team for suggestions. Some cancer programs offer support groups for cancer survivors and their family members right in the clinic or hospital.
  • Calling a nearby cancer center or university hospital and ask about support groups.
  • Contacting a nonprofit cancer organization to request a list of support groups and cancer centers in your area.
  • Contact LIVESTRONG Cancer Navigation Services. Call (855) 220-7777.

If there is pain, day-to-day activities such as putting on shoes or using covers over the feet at night can be difficult. Keep in mind that there are treatments that can lessen the pain. Talk with your health care team about potential treatments as soon as possible.

If neuropathy affects your ability to feel the foot pedals of a car, you should not drive unless your car is adapted for hand controls. Slowed reaction time in moving your foot from the accelerator to the brake pedal may cause an accident. If you lose the ability to drive, you may feel you are losing your independence. However, consider the increased risk to your safety and to the safety of others.

Ask your health care team to provide suggestions and special equipment to make daily tasks safe and easier to manage. The suggestions may include night lights, grab bars and other home safety measures to help reduce the risk of falling. Physical and occupational therapists can assist survivors with physical exercises that can help them maintain physical abilities.

For some, neuropathy can lead to physical and mental stress. Watch for signs of depression, and seek immediate help from your health care team. Together, you can deal with peripheral neuropathy.

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Alphalipoic Acid Prevents Oxidative Stress and Peripheral Neuropathy in Nab-Paclitaxel-Treated Rats through the Nrf2 Signalling Pathway

Abstract

Peripheral neuropathy is the major dose-limiting side effect of paclitaxel (PTX), affecting both the quality of life and the survival of cancer patients. Nab-paclitaxel (nab-PTX) was developed to provide additional clinical benefits and overcome the safety drawbacks of solvent-based PTX. However, the prevalence of peripheral neuropathy induced by nab-PTX was reported higher than that induced by solvent-based PTX. Upon investigation, oxidative stress plays a major role in the toxicity of nab-PTX. In order to assess if the antioxidant alphalipoic acid (α-LA) could prevent the nab-PTX-induced peripheral neuropathy, Sprague-Dawley (SD) rats were treated with three doses of α-LA (15, 30, and 60 mg/kg in normal saline, i.p., q.d. (days 1-30)) and/or nab-PTX (7.4 mg/kg in normal saline, i.v., q.w. (days 8, 15, and 22)). Body weight and peripheral neuropathy were measured and assessed regularly during the study. The assessment of peripheral neuropathy was performed by the von Frey and acetone tests. A tumor xenograft model of pancreatic cancer was used to assess the impact of α-LA on the antitumor effect of nab-PTX. Results showed that α-LA significantly ameliorated the peripheral neuropathy induced by nab-PTX () without promoting tumor growth or reducing the chemotherapeutic effect of nab-PTX in a tumor xenograft model. Moreover, α-LA might significantly reverse the superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) levels altered by nab-PTX in the serum and the spinal cord of rats. Furthermore, α-LA could reverse the mRNA and protein expressions of Nrf2 (nuclear factor erythroid 2-related factor 2) and three Nrf2-responsive genes (HO-1, γ-GCLC, and NQO1) altered by nab-PTX in the dorsal root ganglion (DRG) of rats. In conclusion, our study suggests that α-LA could prevent oxidative stress and peripheral neuropathy in nab-PTX-treated rats through the Nrf2 signalling pathway without diminishing chemotherapeutic effect.

1. Introduction

Paclitaxel (PTX) is classified as a microtubule-binding agent, which is widely used to treat several solid tumors including breast, ovarian, and lung cancers . Its primary antitumor effect occurs by disrupting the mitotic spindle and microtubule dynamics, leading to apoptosis . Peripheral neuropathy, a painful and major dose-limiting side effect of PTX treatment, is predominantly sensory and worsens with cumulative dosing . The typical symptoms of peripheral neuropathy include bilateral numbness, tingling, evoked pain, and spontaneous pain to mechanical and cold stimuli in the hands and/or feet . Peripheral neuropathy can persist for months or years following cessation of PTX. At present, no effective treatments exist to prevent the development of PTX-induced neuropathy or reverse it once established. Therefore, the emergence of peripheral neuropathy during PTX therapy often results in the discontinuation of otherwise successful chemotherapy, thus impacting both the quality of life and the survival of cancer patients .

It was reported that peripheral neuropathy was associated with both the solvent (Cremophor EL) and PTX itself . As a modified formulation of PTX, nanoparticle albumin-bound paclitaxel (nab-PTX) is a water-soluble and Cremophor EL-free formulation of PTX which has no toxicities induced by Cremophor EL . However, various studies, including our preliminary experiment, found that the prevalence and severity of peripheral neuropathy induced by nab-PTX were higher than those induced by solvent-based PTX . Hence, more attention should be given to peripheral neuropathy during nab-PTX treatment. Effective measures must be explored and discovered to prevent the development of peripheral neuropathy induced by nab-PTX.

The exact mechanism of peripheral neuropathy induced by paclitaxel has not been fully elucidated . In recent years, oxidative stress has been considered a significant factor responsible for chemotherapy-induced peripheral neuropathy . Some antioxidants, such as glutathione and N-acetylcysteine, have been used for the prevention and treatment of chemotherapy-induced peripheral neuropathy . As a “universal antioxidant,” alphalipoic acid (α-LA) diminishes the harmful effects of oxidative stress in diabetic neuropathy . Not only does it act on pain, but, as a pathogenesis-oriented treatment, it also improves other symptoms, like paraesthesiae and numbness, along with sensory deficits and muscle strength . In addition, the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element signalling pathway is the main mechanism preventing the effects of oxidative stress. Deleting Nrf2 gene expression led to an increase in neural oxidative stress and rendered relatively less axonal regeneration . Therefore, enhancing nuclear Nrf2 expression and subsequent oxidative stress inhibition may be an important approach in preventing oxidative neural damage and promoting the repair process after peripheral neuropathy. Furthermore, α-LA was reported to attenuate oxidative damage by activating the Nrf2/HO-1 pathway .

Due to the similar pathogenesis between diabetic neuropathy and PTX-induced peripheral neuropathy, α-LA might also have a therapeutic effect on PTX-induced peripheral neuropathy. Considering the severity of peripheral neuropathy induced by nab-PTX compared with solvent-based PTX, the objective of this study was to investigate whether α-LA as a neuroprotective agent and pretreatment can reduce the peripheral neuropathy induced by nab-PTX while determining the underlying molecular mechanisms of the compound’s neuroprotection. Additionally, we sought to determine whether treatment with α-LA would have any effects on the chemotherapeutic effect of nab-PTX.

2. Materials and Methods

2.1. Drugs and Reagents

The alphalipoic acid injection (Yabao Pharmaceutical Group Co. Ltd.), nab-paclitaxel injection (Fresenius Kabi USA, LLC), and normal saline injection (Tianrui Pharmaceutical, Zhejiang, China) were obtained from Zhongshan Hospital of Fudan University (Shanghai, China). The mRNA extraction kit, cDNA extraction kit, RNA amplification kit, primer design, and synthesis were provided by Takara (Takara Bio Inc., Shiga, Japan). Protein antibodies were purchased from Abcam Inc. (Cambridge, MA, USA).

2.2. Experimental Design

Adult male Sprague-Dawley (SD) rats were purchased from Sippr-BK Experimental Animal Center (Shanghai, China) and raised under standard conditions of animal housing (a 12-hour light/dark cycle, temperature 25°C, and humidity 55–60%) with free access to food and water. All animal care and experimental protocols were conducted in accordance with the Institutional Animal Care and Use Committee (IACUC), School of Pharmacy, Fudan University. The ethical approval was shown in Supplementary File 1. The experimental procedures complied with the recommendations of the International Association for the Study of Pain . All efforts were made to minimize the number of animals used and their suffering. After 1 week of circumstance adaption, SD rats were randomly assigned to 5 groups according to body weight: vehicle (normal saline), nab-PTX (7.4 mg/kg in normal saline, i.v., q.w (days 8, 15, and 22)), and nab-PTX (7.4 mg/kg in normal saline, i.v., q.w. (days 8, 15, and 22)) combined with three doses of α-LA (low dose,15 mg/kg; middle dose, 30 mg/kg; and high dose, 60 mg/kg, respectively, in normal saline, i.p., q.d. (days 1-30)) (Supplementary Figure 1). The body weight of rats was measured every 3 to 4 days. The assessment of peripheral neuropathy was performed blind with respect to the drug administration on days 8, 15, 22, and 29 (days 1, 7, 14, and 21 after nab-PTX administration). The animals were double-labelled, and then, the final data was back-analyzed with the original groups of the animals.

2.3. von Frey Test for Mechanical Allodynia

All rats were allowed to acclimate for approximately 30 minutes before testing. The mechanical paw withdrawal threshold was assessed using the von Frey filaments (U.S. North Coast, NC12775-99). Each rat was placed in a chamber () with a customized platform made of iron wires, which create a 10 mm grid throughout the entire area. A series of 7 calibrated von Frey filaments were applied to the central region of the plantar surface of one hind paw in ascending order (1, 2, 4, 6, 8, 10, and 15 g) with the highest filament at 15 g. Each filament was applied to the midplanter skin of each hind paw five times until the force slightly bent the tip and was then held for 5 seconds. A trial consisted of applying a von Frey filament to the hind paw 5 times at 15 sec intervals. When the hind paw withdrew from a particular filament in 4 of the 5 consecutive applications, the value of that filament in grams was considered to be the paw withdrawal threshold (PWT). Withdrawal responses from both hind paws were counted, and the percentage response was calculated as previously described . The test was performed on days 1, 7, 14, and 21 after nab-PTX administration.

2.4. Acetone Test for Cold Hypersensitivity

The responses to an acetone droplet on the hind paw were measured for the assessment of cold hypersensitivity . The use of acetone for cold hypersensitivity in the peripheral and central neuropathic pain animal models was examined and suggested to be similar to the response seen in human neuropathic pain patients who suffered from mechanical and cold hypersensitivity in previous studies . The rats were placed in individual areas and allowed to acclimate for at least 30 minutes. For testing, 50 μl of acetone was applied to the plantar skin of the rat’s hind paw slowly over a period of 2–3 seconds by a pipette. The injured rats quickly lifted and vigorously shook the paw after the application of the acetone to the hind paw. The uninjured rats generally showed no lifting response to the application. Both the left and right hind paws were tested with at least 5 minutes between each application of acetone. The frequency of responses was calculated from the number of times the rat responded to an acetone application to the hind paw skin out of 5 trials (). Only reflexive responses that also included head orientation, vocalization, or grooming of the tested limb were counted as a positive response.

2.5. Oxidative Activity Evaluation by Biochemical Assessment

As markers of oxidative stress, the superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) levels of the serum and the spinal cord of the SD rats were measured by a microplate reader (Thermo Fisher Scientific) using the assay kits (Nanjing Jiancheng Bioengineering Research Institute, Nanjing, China) according to the procedure recommended by the manufacturer (SOD, 450 nm; GSH, 405 nm; and MDA, 530 nm). The concentrations of SOD, GSH, and MDA were calculated in nanomoles per gram of protein.

2.6. Western Blotting

After mechanical and cold allodynia testing on day 21, the rats were deeply anesthetized with an i.p. injection of 10% chloral hydrate. For RNA assays, the bilateral DRGs (L4-6) were harvested, immediately frozen with liquid nitrogen, and then stored at -80°C. Proteins were extracted from DRGs by cell lysis buffer for Western blotting and IP (Dalian Meilun Biological Technology Co. Ltd, China) according to the manufacturer’s protocol. Protein concentrations were measured using a bicinchoninic acid (BCA) protein assay kit (Beyotime, Jiangsu, China). Total protein was electrophoresed in a 10% SDS-PAGE gel and transferred onto polyvinylidene difluoride (PVDF) membranes (Millipore, US). The membranes were blocked with 5% nonfat milk in TBST. The membranes were incubated with specific primary antibodies overnight at 4°C. After the membranes were washed with PBST, they were incubated with HRP-conjugated secondary antibodies for 2 hours at room temperature and then washed 3 more times again. The antigen-antibody complexes were detected by enhanced chemiluminescence (ECL) (Amersham Life Science, England) and visualized by Bio-Rad ChemiDoc XRS (Bio-Rad, USA).

2.7. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR)

The total RNA of the bilateral dorsal root ganglions (DRGs) (L4-6) was isolated by RNAiso Plus (Takara Bio Inc., Shiga, Japan) according to the manufacturer’s instruction. The first-strand cDNA was generated using the PrimerScript™ RT Reagent kit with gDNA Eraser (Takara Bio Inc., Shiga, Japan). The sequences of the primers used for Nrf2, HO-1, γ-GCLC, NQO1, and GAPDH were shown in Table 1. The Bio-Rad iCycler qPCR system and TB Green Premix EX Taq II (Takara Bio Inc., Shiga, Japan) were used to perform qPCR. The cycling conditions for all primer pairs were as follows: 5 seconds at 95°C and 30 seconds at 60°C, according to the manufacturer’s protocol. The ratios of Nrf2, HO-1, γ-GCLC, and NQO1 mRNA expressions to the GAPDH level in each sample were considered to be the mRNA levels and were expressed relative to the mRNA levels of the control group. Data were shown as deviation.

Gene Sequences of primers
Nrf2 Forward: 5-TTGGCAGAGACATTCCCATTTGTA-3
Reverse: 5-GAGCTATCGAGTGACTGAGCCTGA-3
HO-1 Forward: 5-AGGTGCACATCCGTGCAGAG-3
Reverse: 5-CTTCCAGGGCCGTATAGATATGGTA-3
γ-GCLC Forward: 5-CTGCACATCTACCACGCAGTCA-3
Reverse: 5-ATCGCCGCCATTCAGTAACAA-3
NQO1 Forward: 5-TGGAAGCTGCAGACCTGGTG-3
Reverse: 5-CCCTTGTCATACATGGTGGCATAC-3
GAPDH Forward: 5-GGCACAGTCAAGGCTGAGAATG-3
Reverse: 5-ATGGTGGTGAAGACGCCAGTA-3

Table 1 Sequences of the primers used for Nrf2, HO-1, γ-GCLC, NQO1, and GAPDH.

2.8. Chemotherapeutic Effect Evaluation

After determining the neuroprotective effects of α-LA, we further investigated whether treatment with α-LA would have any effects on the chemotherapeutic effect of nab-PTX through the establishment of a subcutaneous xenograft model of pancreatic cancer.

The pancreatic cancer cell line CFPAC-1 was purchased from the Cell Bank of Shanghai Institute of Cell Biology, Chinese Academy of Sciences (Shanghai, China). CFPAC-1 cells were cultured in IMDM (Hyclone, China) with 10% (v/v) FBS and incubated at 37°C in 5% CO2 in a CO2 incubator (Thermo Scientific Forma). Cells were routinely checked for Mycoplasma contamination.

2.9. Statistical Analysis

Experimental data were presented as deviation from at least 3 independent experiments. One-way ANOVA followed by S-N-K multiple comparisons was used to evaluate the statistical significance of the differences among multiple groups in vitro, and one-way ANOVA followed by Dunnett’s multiple comparisons was applied to the in vivo comparisons among multiple groups. A value less than 0.05 was considered to be statistically significant.

3. Results

3.1. Body Weight and Peripheral Neuropathy Assessment

The administration of alphalipoic acid, nab-paclitaxel, and vehicle was well tolerated by the rats, without any cases of mortality. Rats that received nab-paclitaxel showed a slight but insignificant reduction in body weight compared with that of the controls (Supplementary Figure 3).

Mechanical and cold allodynia were tested on days 1, 4, 7, 14, and 21 after nab-PTX administration. As shown in Figure 1(a), the bilateral paw withdrawal thresholds of rats in the nab-PTX-treated group decreased significantly following nab-PTX compared with those in the vehicle group (), indicating a mirror-like mechanical allodynia. In the 4, 8, and 15 g von Frey tests, nab-PTX-treated rats showed significantly more responses than the controls (Figure 1(c)). The acetone test for cold allodynia also indicated that nab-PTX-treated rats showed significantly more responses than the controls (, Figure 1(b)). Furthermore, we investigated whether α-LA could ameliorate neuropathic pain and cold allodynia induced by nab-PTX. Our results indicated that all 3 dosage regimens (15, 30, and 60 mg/kg) of α-LA had significant effects on neuropathic pain induced by nab-PTX (, Figure 1(a)). The mechanical withdrawal thresholds of rats treated with α-LA (three dosage regimens) plus nab-PTX increased significantly compared with those of the single nab-PTX-treated ones. In the 4, 8, and 15 g von Frey tests, the rats treated with α-LA plus nab-PTX displayed significantly reduced responses than the single nab-PTX-treated group (, Figure 1(c)). The cold withdrawal responses of α-LA plus nab-PTX-treated rats were also significantly reduced compared with those of the single nab-PTX-treated ones (, Figure 1(b)).

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(c) Figure 1 Changes of mechanical and cold withdrawal responses in rats. , nab-PTX versus vehicle group; , nab-PTX versus vehicle group; , α-LA (low dose)+nab-PTX versus nab-PTX group, , α-LA (low dose)+nab-PTX versus nab-PTX group; , α-LA (middle dose)+nab-PTX versus nab-PTX group; , α-LA (middle dose)+nab-PTX versus nab-PTX group; , α-LA (high dose)+nab-PTX versus nab-PTX group; and , α-LA (high dose)+nab-PTX versus nab-PTX group.

3.2. Alphalipoic Acid Inhibits Oxidative Stress in Nab-Paclitaxel-Treated Rats

The oxidative activities in the serum and spinal cord tissues of rats were measured. The contents of SOD and GSH in both serum and spinal cord tissues were significantly decreased by nab-PTX, suggesting that nab-PTX could disrupt the antioxidant defense systems in the serum and the spinal cord. However, activities of SOD and GSH in both serum and spinal cord tissues could be restored by α-LA administration at 3 dosage regimens (15, 30, and 60 mg/kg), respectively (Figures 2(a), 2(b), 2(d), and 2(e)). The contents of MDA in both serum and spinal cord tissues were significantly increased by nab-PTX but significantly decreased by α-LA (Figures 2(c) and 2(f)).

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(f) Figure 2 The oxidative activities of the serum and spinal cord tissues in rats. versus vehicle group, versus vehicle group, versus nab-PTX group, and versus nab-PTX group.

3.3. Alphalipoic Acid Activates the Nrf2 Pathway in Nab-Paclitaxel-Treated Rats

Compared with the controls, the protein levels of Nrf2, HO-1, and NQO1 in DRGs decreased significantly in the nab-PTX-treated mice. Cotreatment with α-LA significantly increased Nrf2, HO-1, and NQO1 protein expressions in the DRGs (Figure 3). The mRNA levels of Nrf2, HO-1, γ-GCLC, and NQO1 were significantly decreased by nab-PTX, and α-LA administration upregulated the mRNA expressions of these Nrf2 target genes (Figure 4).

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(d) Figure 3 The protein expression of Nrf2, HO-1, and NQO1 of DRGs in rats. versus vehicle group, versus vehicle group, versus nab-PTX group, and versus nab-PTX group.
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(d) Figure 4 The mRNA levels of Nrf2, HO-1, γ-GCLC, and NQO1 of DRGs in rats. (a) Nrf2, (b) HO-1, (c) γ-GCLC, and (d) NQO1. versus vehicle group, versus vehicle group, versus nab-PTX group, and versus nab-PTX group.

3.4. Alphalipoic Acid Does Not Reverse the Antitumor Effect of Nab-Paclitaxel in a Mouse Xenograft Model

The administration of α-LA (60 mg/kg), nab-PTX (7.4 mg/kg), or vehicle was well tolerated by the mice, without any cases of mortality. The body weight of the mice in the 4 groups had no significant differences (Supplementary Figure 4), indicating that α-LA and nab-PTX had no significant impact on the body weight of the mice in our experiment.

As shown in Figure 5(a), we found that the growth of CFPAC-1 xenograft tumor was inhibited significantly by α-LA as compared with that of controls (). However, combinational use of α-LA and nab-PTX caused no significant growth inhibition compared with that of single nab-PTX, indicating that α-LA had no additional effect on the antitumor effect of nab-PTX. Comparisons of the tumor weight in each group found that the tumor weight of α-LA-treated mice was significantly lighter than that of the controls (, Figures 5(b) and 5(c)). In addition, although there was no significant difference of tumor weight between α-LA plus nab-PTX and single nab-PTX groups, the tumor weight of α-LA plus nab-PTX-treated mice tended to be lighter than that of the single nab-PTX-treated ones (Figure 5(c)).

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(c) Figure 5 Tumor volume changes and tumor weight of mice.

4. Discussion

The management of peripheral neuropathy induced by many commonly used chemotherapeutic agents, such as taxanes and platinum drugs, continues to be an important challenge for both clinicians and cancer patients, because it can be extremely painful and/or disabling, causing significant loss of functional abilities and decreasing the quality of life . The current standard care of cancer patients includes the dose reduction and/or discontinuation of chemotherapy treatment which influences chemotherapeutic effect and survival of cancer patients .

As a new formulation of PTX, nab-PTX is widely used in clinical practice with a better chemotherapeutic effect and no solvent-related toxicities . However, nab-PTX was reported to have a higher prevalence and severity of peripheral neuropathy in several studies . Our meta-analysis indicated that the incidence of all-grade peripheral neuropathy in cancer patients receiving nab-PTX and solvent-based PTX was 65% (95% CI, 47%-80%) and 54% (95% CI, 44%-63%), respectively. Additionally, the incidence of high-grade peripheral neuropathy between nab-PTX and solvent-based PTX was 16% (95% CI, 11%-23%) and 5% (95% CI, 3%-8%), respectively () (unpublished). Therefore, great attention must be paid to the peripheral neuropathy accompanying the use of nab-PTX in clinical practice. Yet, due to the scarcity of conclusive evidence, no agent is currently recommended for the treatment or prophylaxis of nab-PTX-induced peripheral neuropathy.

Currently, the underlying mechanism of peripheral neuropathy induced by PTX is not entirely understood. Oxidative stress has been known as an imbalance between the free radicals and antioxidant defense system. Neurons were more sensitive to oxidative stress because of the low activity of antioxidant enzymes . Experimental studies supported that there was evidence about PTX-induced neuropathy related to oxidative stress . Alphalipoic acid (α-LA) is a physiologic antioxidant that has been examined quite extensively as a treatment for diabetic neuropathy. Moreover, α-LA was effective in the treatment of distal sensory motor neuropathy, as well as in the modulation of peripheral neuropathy and pain reduction in diabetic patients . α-LA could also ameliorate the docetaxel/cisplatin-induced polyneuropathy . The neuroprotective mechanism of α-LA was related to the reduction of oxidative stress from free radical formation . Experimental evidence suggested that α-LA could restore the glutathione levels, prevent lipid peroxidation, increase the activity of antioxidant enzymes (such as catalase and superoxide dismutase in peripheral nerves), and increase the blood flow, glucose uptake, and metabolism in peripheral nerves along with nerve conduction velocity (NCV) . Moreover, α-LA could correct the deficits of neuropeptides (such as substance P and Neuropeptide Y) in the spinal cord and restrain the activation of NF-κB in peripheral nerves . α-LA could also exert a neuroprotective action against the reperfusion injury , promote the activity of adenosine triphosphate , reduce the excess lipid oxidation , and ameliorate hyperalgesia . In addition, α-LA could protect sensory neurons through its antioxidant and mitochondrial regulatory functions in vitro . Although α-LA could ameliorate diabetic neuropathy and peripheral neuropathy induced by various types of chemotherapy drugs, it is still unclear whether α-LA could have neuroprotective effects on nab-PTX-induced peripheral neuropathy because of the different pathogenic mechanisms .

Our study has shown that α-LA could significantly ameliorate neuropathic pain and cold allodynia induced by nab-PTX in rats via Nrf2 activation and oxidative stress inhibition, suggesting that α-LA ameliorated the peripheral neuropathy in this experimental model by protecting against oxidative system damage caused by nab-PTX. Although our experimental number of 6 per group sounds small to permit consistent conclusions for behavioral assessments, the results of power analysis indicate that it is acceptable in the present study (data not shown). After determining the neuroprotective effects of α-LA, we were not sure whether α-LA could influence the chemotherapeutic effect of nab-PTX. Therefore, we established a subcutaneous xenograft model of pancreatic cancer and found that α-LA had a potential antitumor effect, although the antitumor effect was not significant when combined with nab-PTX. Several studies also indicated that α-LA could sensitize lung cancer cells to chemotherapeutic agents , promote synergistic antitumor effects , and inhibit breast cancer cell proliferation .

Although our study has confirmed that α-LA could ameliorate the peripheral neuropathy induced by nab-PTX without diminishing the chemotherapeutic effect, there are still some limitations in our study. First, our study was done in rats and whether this conclusion is also applicable to humans would require further study. Additionally, we established a subcutaneous xenograft model of pancreatic cancer; whether the results could also be consistent in the orthotopic xenograft tumor model in consideration of the complexity of pancreatic cancer, further research needs to be performed.

5. Conclusions

In conclusion, the data presented here suggests that α-LA could significantly prevent oxidative stress and peripheral neuropathy in nab-PTX-treated rats through the Nrf2 signalling pathway without diminishing the chemotherapeutic effect of nab-PTX in a subcutaneous xenograft tumor model. To employ this inexpensive, relatively safe neuroprotective drug in chemotherapeutic regimens that induce neuropathy, larger preclinical and clinical studies need to be performed.

Data Availability

All the data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest

The authors report no conflict of interests.

Authors’ Contributions

Hong Sun and Xi Guo contributed equally to this work.

Acknowledgments

The authors thank Lacey Brinegar, Ryan Jenks, and Anders Nguyen for their comments and careful review of the manuscript.

Supplementary Materials

Figure S1: experimental groups and protocol of study on neurotoxicity protection by α-LA. Figure S2: experimental groups and protocol of study on antitumor effect by α-LA. Figure S3: changes of body weight (g) in rats. Figure S4: changes of body weight (g) in nude mice. Supplementary File 1: Experimental Animals Ethics Committee of School of Pharmacy Fudan University. (Supplementary Materials)

Treating Nerve Pain

When nerve pain is caused by a condition like diabetes, HIV or cancer, getting treatment for the underlying disease is obviously the priority.

But treatments for the underlying disease might not necessarily help with your pain. Nerve pain may need its own treatment, separate from treatment for the disease that’s causing it.

The most effective and suitable treatment for nerve pain varies, because it depends on the specifics — like the patient’s health, the underlying cause, the risks of potential side effects, and the costs. However, doctors generally use the same set of treatments for nerve pain, whether it is caused by cancer, HIV, diabetes, or another condition. Here’s a rundown of the basic options.

  • Topical treatments. Some over-the-counter and prescription topical treatments — like creams, lotions, gels, and patches — can ease nerve pain. They tend to work best for pain that’s isolated in specific areas on your skin.
  • Anticonvulsants. These drugs were originally developed to treat epilepsy, but some also help control nerve pain. To boost their effects, they are often used in combination with antidepressants. They might not work as well with all types of nerve pain.
  • Antidepressants . Certain types of antidepressants can help with nerve pain. Studies have shown that using them along with anticonvulsants may have bigger benefits than using them alone. However, some studies have indicated that while tricyclic antidepressants may help with diabetic nerve pain, they might not help with nerve pain caused by HIV or cancer chemotherapy.
  • Painkillers. Powerful opioid painkillers might be a first choice for people with especially severe pain or nerve pain caused by cancer. However, for other kinds of nerve pain, doctors generally try anti-inflammatories or pain relievers, or antidepressants and/or anticonvulsants first. Opioids can have serious side effects. Over-the-counter painkillers may not work very well for moderate to severe nerve pain.
  • Electrical stimulation. A number of treatments use electrical impulses to block the pain messages sent by damaged nerves. These include TENS (transcutaneous electrical nerve stimulation) and repetitive transcranial magnetic stimulation (rTMS.) Both are noninvasive and painless. Some other electrical stimulation approaches are more complex and require surgery.
  • Other techniques. In certain cases, doctors might recommend injections of anesthetic or, rarely, surgery to tackle nerve pain.
  • Complementary treatments. Many people find that alternative approaches — like acupuncture, meditation, and massage — can help relieve nerve pain. If you’re interested in dietary supplements for nerve pain, talk to your doctor first.
  • Lifestyle changes. While they won’t cure nerve pain, making some changes to your habits could help you feel better and ease some of your discomfort. Exercising more, eating a healthy diet, quitting smoking, and making time to practice relaxation techniques could all help.

When nerves get damaged

Updated: April 3, 2019Published: July, 2010

Peripheral neuropathy causes strange feelings of numbness and sometimes pain.

We’ve all had a foot fall asleep because of the way we have been sitting or standing. The abnormal pressure pushes on nerves and compresses the blood vessels that supply them. The nerves react to their distress by sending signals that cause an unpleasant, even painful, tingling sensation. But it’s a temporary situation: the pins-and-needles go away after we change position so blood vessels open up and the pressure is off the nerve – unless you suffer from peripheral neuropathy.

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Key mechanism that causes neuropathic pain found

A biological process called endoplasmic reticulum stress, or ER stress, is the significant driver of neuropathic pain, said lead researchers Bora Inceoglu of the UC Davis Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, and Ahmed Bettaieb, Department of Nutrition. The work is published July 6 in the journal Proceedings of the National Academy of Sciences.

“This is a fundamental discovery that opens new ways to control chronic pain,” said co-author Bruce Hammock, distinguished professor at the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.

“We can now specifically search for agents to control ER stress and its downstream pathways,” Hammock said. “This search is already underway in a number of laboratories working on cancer and other diseases.”

Working with Professor Fawaz Haj of the UC Davis nutrition department, Bettaieb found that key molecular signatures associated with diabetes and diabetic pain were linked to ER stress. Neuropathic pain is a common consequence of both Type 1 and Type 2 diabetes, affecting up to 70 percent of patients.

Inceoglu, working in Hammock’s laboratory, showed that neuropathic pain could be initiated by compounds that cause ER stress and reversed by agents that block it.

The researchers had previously shown that a class of natural bioactive lipids has powerful analgesic effects in the body. These analgesic lipids are broken down in the body by an enzyme, soluble epoxide hydrolase. The team was able to show that blocking soluble epoxide hydrolase blocks ER stress and associated neuropathic pain.

The work sheds new light onto at least one biological process that mediates neuropathic pain, Inceoglu said. With this knowledge, researchers can now test ER-stress blocking drugs in the clinic, and carry out fundamental research on how different types of pain grouped under the name “neuropathic” differ from each other and respond to new drugs.

The study provides convincing evidence for a novel concept as to what causes neuropathic pain said John Imig, professor of pharmacology and toxicology at the Medical College of Wisconsin, Milwaukee, who was not involved in the study. The work provides new opportunities for drugs or drug combinations to treat chronic pain, he said.

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