Phytic Acid Maintains Peripheral Neuron Integrity and Enhances Survivability against Platinum-Induced Degeneration via Reducing Reactive Oxygen Species and Enhancing Mitochondrial Membrane Potential.

Phytic acid (PA) has been reported to possess anti-inflammatory and antioxidant properties that are critical for neuroprotection in neuronal disorders. This raises the question of whether PA can effectively protect sensory neurons against chemotherapy-induced peripheral neuropathy (CIPN). Peripheral neuropathy is a dose-limiting side effect of chemotherapy treatment often characterized by severe and abnormal pain in hands and feet resulting from peripheral nerve degeneration. Currently, there are no effective treatments available that can prevent or cure peripheral neuropathies other than symptomatic management. Herein, we aim to demonstrate the neuroprotective effects of PA against the neurodegeneration induced by the chemotherapeutics cisplatin (CDDP) and oxaliplatin. Further aims of this study are to provide the proposed mechanism of PA-mediated neuroprotection. The neuronal protection and survivability against CDDP were characterized by axon length measurements and cell body counting of the dorsal root ganglia (DRG) neurons. A cellular phenotype study was conducted microscopically. Intracellular reactive oxygen species (ROS) was estimated by fluorogenic probe dichlorofluorescein. Likewise, mitochondrial membrane potential (MMP) was assessed by fluorescent MitoTracker Orange CMTMRos. Similarly, the mitochondria-localized superoxide anion radical in response to CDDP with and without PA was evaluated. The culture of primary DRG neurons with CDDP reduced axon length and overall neuronal survival. However, cotreatment with PA demonstrated that axons were completely protected and showed increased stability up to the 45-day test duration, which is comparable to samples treated with PA alone and control. Notably, PA treatment scavenged the mitochondria-specific superoxide radicals and overall intracellular ROS that were largely induced by CDDP and simultaneously restored MMP. These results are credited to the underlying neuroprotection of PA in a platinum-treated condition. The results also exhibited that PA had a synergistic anticancer effect with CDDP in ovarian cancer in vitro models. For the first time, PA's potency against CDDP-induced PN is demonstrated systematically. The overall findings of this study suggest the application of PA in CIPN prevention and therapeutic purposes.

Electrical stimulation enhances mitochondrial trafficking as a neuroprotective mechanism against chemotherapy-induced peripheral neuropathy.

Electrical stimulation (ESTIM) has shown to be an effective symptomatic treatment to treat pain associated with peripheral nerve damage. However, the neuroprotective mechanism of ESTIM on peripheral neuropathies is still unknown. In this study, we identified that ESTIM has the ability to enhance mitochondrial trafficking as a neuroprotective mechanism against chemotherapy-induced peripheral neuropathies (CIPNs). CIPN is a debilitating and painful sequalae of anti-cancer chemotherapy treatment which results in degeneration of peripheral nerves. Mitochondrial dynamics were analyzed within axons in response to two different antineoplastic mechanisms by chemotherapy drug treatments paclitaxel and oxaliplatin in vitro. Mitochondrial trafficking response to chemotherapy drug treatment was observed to decrease in conjunction with degeneration of distal axons. Using low-frequency ESTIM, we observed enhanced mitochondrial trafficking to be a neuroprotective mechanism against CIPN. This study confirms ESTIM enhances regeneration of peripheral nerves by increased mitochondrial trafficking.

Mitochondrial trafficking as a protective mechanism against chemotherapy drug-induced peripheral neuropathy: Identifying the key site of action.

AIMS: Chemotherapy induced peripheral neuropathy (CIPN) is a common side effect seen in patients who have undergone most chemotherapy treatments to which there are currently no treatment methods. CIPN has been shown to cause axonal degeneration leading to Peripheral Neuropathy (PN), which can lead to major dosage reduction and may prevent further chemotherapy treatment due to oftentimes debilitating pain. Previously, we have determined the site-specific action of Paclitaxel (PTX), a microtubule targeting agent, as well as the neuroprotective effect of Fluocinolone Acetonide (FA) against Paclitaxel Induced Peripheral Neuropathy (PIPN). MAIN METHODS: Mitochondrial trafficking analysis was determined for all sample sets, wherein FA showed enhanced anterograde (axonal) mitochondrial trafficking leading to neuroprotective effects for all samples. KEY FINDINGS: Using this system, we demonstrate that PTX, Monomethyl auristatin E (MMAE), and Vincristine (VCR), are toxic at clinically prescribed levels when treated focally to axons. However, Cisplatin (CDDP) was determined to have a higher toxicity when treated to cell bodies. Although having different targeting mechanisms, the administration of FA was determined to have a significant neuroprotective effect for against all chemotherapy drugs tested. SIGNIFICANCE: This study identifies key insights regarding site of action and neuroprotective strategies to further development as potential therapeutics against CIPN. FA was treated alongside each chemotherapy drug to identify the neuroprotective effect against CIPN, where FA was found to be neuroprotective for all drugs tested. This study found that treatment with FA led to an enhancement in the anterograde movement of mitochondria based on fluorescent imaging.

A review on current brain organoid technologies from a biomedical engineering perspective.

Brain organoids are 3D cytoarchitectures resembling the embryonic human brain. This review focuses on current advancements in biomedical engineering methods to develop organoids such as pluripotent stem cells assemblies, quickly aggregated floating culture, hydrogel suspension, microfluidic systems (both photolithography and 3D printing), and brain organoids-on-a-chip. These methods have the potential to create a large impact on neurological disorder studies by creating a model of the human brain investigating pathogenesis and drug screening for individual patients. 3D brain organoid cultures mimic not only features of patients' unknown drug reactions, but also early human brain development at cellular, structural, and functional levels. The challenge of current brain organoids lies in the formation of distinct cortical neuron layers, gyrification, and the establishment of complex neuronal circuitry, as they are critically specialized, developmental aspects. Furthermore, recent advances such as vascularization and genome engineering are in development to overcome the barrier of neuronal complexity. Future technology of brain organoids is needed to improve tissue cross-communication, body axis simulation, cell patterning signals, and spatial-temporal control of differentiation, as engineering methods discussed in this review are rapidly evolving.

Fluocinolone Acetonide Enhances Anterograde Mitochondria Trafficking and Promotes Neuroprotection against Paclitaxel-Induced Peripheral Neuropathy.

Paclitaxel (PTX)-induced peripheral neuropathy (PIPN) is a debilitating health condition which is a result of degeneration of peripheral nerves found in extremities. Currently, there are no established treatment methods that can prevent or protect from PIPN. Fluocinolone acetonide (FA) has been recently identified as a potential candidate for protection from PIPN. However, the fundamental mechanism of action is still unknown. In this study, we showed that enhanced anterograde mitochondrial movement in dorsal root ganglion (DRG) cells has a major role in FA-mediated neuroprotection in PIPN. In this study, cells were treated with PTX or FA along with their combination followed by mitochondrial fluorescence staining. Somal (proximal) and axonal (distal) mitochondria were selectively stained using a microfluidic compartmentalized chamber with different MitoTrackers blue and red, respectively, which we termed, the two-color staining approach. Results revealed that axons were protected from degeneration by the PTX effect when treated along with FA. PTX exposure alone resulted in low mitochondrial mobility in DRG cells. However, cotreatment with PTX and FA showed significant enhancement of anterograde trafficking of somal (proximal) mitochondria to distal axons. Similarly, cotreatment with FA restored mitochondrial mobility significantly. Overall, this study affirms that increasing mitochondrial recruitment into the axon by cotreatment with FA can be a worthwhile strategy to protect or prevent PIPN. The proposed two-color staining approach can be extended to study trafficking for other neuron-specific subcellular organelles.

A Review on the Technological Advances and Future Perspectives of Axon Guidance and Regeneration in Peripheral Nerve Repair.

Despite a significant advance in the pathophysiological understanding of peripheral nerve damage, the successful treatment of large nerve defects remains an unmet medical need. In this article, axon growth guidance for peripheral nerve regeneration was systematically reviewed and discussed mainly from the engineering perspective. In addition, the common approaches to surgery, bioengineering approaches to emerging technologies such as optogenetic stimulation and magnetic stimulation for functional recovery were discussed, along with their pros and cons. Additionally, clear future perspectives of axon guidance and nerve regeneration were addressed.