Collaborative Roles for RAC1, ERM Proteins and PTEN During Adult Sensory Axon Regeneration.

The role of local of growth cone (GC) manipulation in adult regenerative systems is largely unexplored despite substantial translational importance. Here we investigated collaboration among Rac1 GTPase, its partnering ERM proteins and PTEN in adult sensory neurons and adult nerve regeneration. We confirmed expression of both Rac1 and ERM in adults and noted substantial impacts on neurite outgrowth in naïve and pre-injured adult sensory neurons.

Manipulation of the Myc Interactome to Enhance Nerve Regeneration in a Murine Model.

Objective: This study was undertaken to explore manipulation of the Myc protein interactome, members of an oncogene group, in enhancing the intrinsic growth of injured peripheral adult postmitotic neurons and the nerves they supply. New approaches to enhance adult neuron growth properties are a key strategy in improving nerve regeneration.

Methods: Expression and impact of Myc interactome members c-Myc, N-Myc, Mad1, and Max were evaluated within naive and "preconditioned" adult sensory neurons and Schwann cells (SCs), using siRNA and transfection of CRISPR/Cas9 or luciferase reporter in vitro.

The Role of Protocadherin γ in Adult Sensory Neurons and Skin Reinnervation.

The clustered protocadherins (cPcdhs) play a critical role in the patterning of several CNS axon and dendritic arbors, through regulation of homophilic self and neighboring interactions. While not explored, primary peripheral sensory afferents that innervate the epidermis may require similar constraints to convey spatial signals with appropriate fidelity. Here, we show that members of the γ-Pcdh (Pcdhγ) family are expressed in both adult sensory neuron axons and in neighboring keratinocytes that have close interactions during skin reinnervation.

Combined PTEN Knockdown and Local Insulin in Chronic Experimental Diabetic Neuropathy.

Unlabelled: Diabetic polyneuropathy (DPN) renders progressive sensory neurodegeneration linked to hyperglycemia and its associated metabolopathy. We hypothesized that there may be additive impacts of direct insulin signaling, independent of glycemia and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) knockdown on neuropathy. Our targets for combined interventions were neurons and Schwann cells (SCs) in vitro and chronic type 1 DPN in mice.

Survival of compromised adult sensory neurons involves macrovesicular formation.

Adult neurons are recognized as post-mitotically arrested cells with limited regenerative potential. Given these restraints, it is perplexing how neurons sustain routine physiological and occasional reparative stress without compromising their density and integrity. We observed that specific insults or physiological alterations drive adult sensory neurons to attempt cell cycle entry.

Neuroprotective Effect of Baicalein Against Oxaliplatin-Induced Peripheral Neuropathy: Impact on Oxidative Stress, Neuro-inflammation and WNT/β-Catenin Signaling.

Oxaliplatin, an effective anti-cancer agent used in the treatment of colorectal cancer, is associated with severe dose-limiting side effects like peripheral neuropathy, which currently remains a major unmet clinical need. This study was designed to investigate the possible neuroprotective potential of a bioflavonoid, baicalein in an experimental model of oxaliplatin-induced peripheral neuropathy. Rats were administered with a dose of 4 mg/kg oxaliplatin i.

FeTMPyP a peroxynitrite decomposition catalyst ameliorated functional and behavioral deficits in chronic constriction injury induced neuropathic pain in rats.

Neuropathic pain is a maladaptive pain phenotype that results from injury or damage to the somatosensory nervous system and is proposed to be linked to a cascade of events including excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation and apoptosis. Oxidative/nitrosative stress is a critical link between neuroinflammation and neurodegeneration through poly (ADP) ribose polymerase (PARP) overactivation. Hence, the present study investigated the antioxidant and anti-inflammatory effects of peroxynitrite decomposition catalyst; FeTMPyP in chronic constriction injury (CCI) of sciatic nerve-induced neuropathy in rats.

In vitro priming response in dorsal root ganglia partially mimics injury-driven pre-conditioning response and reprograms neurons for enhanced outgrowth.

Peripheral nerve injuries have the potential to bring about long-term disabilities in individuals. The major issue in repairing nerve injuries is the poor growth rate of axons. Although several molecules have been identified as potential candidates for improving axon growth, their potential translation into clinical practice is preliminary and largely unexplored.

Dual Specificity Phosphatases Support Axon Plasticity and Viability.

In peripheral neuropathies, axonal degeneration (AxD) impairs the prognosis for recovery. Here, we describe a role for dual specificity phosphatases (DUSPs; MAP kinase phosphatases, MKPs), in supporting autonomous axon plasticity and viability. Both DUSPs 1 and 4 were identified within intact or axotomized sensory neurons.

Rosmarinic Acid Mitigates Mitochondrial Dysfunction and Spinal Glial Activation in Oxaliplatin-induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting complication which develops as a consequence of treatment with chemotherapeutic agents like oxaliplatin and is a mainstay of therapy for colorectal cancer. Ever since CIPN was identified, understanding its exact pathomechanisms remains a clinical challenge. The role of mitochondrial dysfunction and glial cell activation has surfaced in the etiology of CIPN.

Adenosine monophosphate-activated protein kinase modulation by berberine attenuates mitochondrial deficits and redox imbalance in experimental diabetic neuropathy.

Adenosine monophosphate-activated protein kinase (AMPK) has been studied for its myriad metabolic and mitochondrial benefits in several chronic diseases. Recent studies have uncovered its therapeutic potential against mitochondrial dysfunction in cultured dorsal root ganglion (DRG) neurons isolated from streptozotocin (STZ) induced diabetic rats. The present study is aimed at evaluating the pharmacological efficacy of berberine (BRB), a natural AMPK activator against experimental diabetic neuropathy (DN) phenotype developed in STZ (55 mg/kg, i.

Morin exerts neuroprotection via attenuation of ROS induced oxidative damage and neuroinflammation in experimental diabetic neuropathy.

Morin, a bioflavonoid with diverse pharmacological effects against various diseases; in most cases morin protective effects were attributed to its detoxifying effect against reactive oxygen species (ROS). Diabetic neuropathy (DN) is a chronic, debilitating neuronal pain associated with intense generation of free radicals and proinflammatory cytokine accumulation in peripheral neurons. We investigated the pharmacological effect of morin against metabolic excess mediated mitochondrial ROS generation and corresponding effect on Nrf2, NF-κB pathways in Streptozotocin (STZ)-induced diabetic rats and in high glucose insulted Mouse neuroblastoma cell line, Neuro 2A (N2A).

Nrf2 and NF-κB modulation by Plumbagin attenuates functional, behavioural and biochemical deficits in rat model of neuropathic pain.

Background: Plumbagin is known to exhibit a broad range of biological activities including anti-cancer, antimicrobial and has been widely used traditionally. Nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) inhibitory and Nuclear factor (erythroid derived-2) like-2 (Nrf2) modulatory activities of Plumbagin have been reported already. In nerve injury model of neuropathy in rats, the role of NF-κB upregulation and declined antioxidant defence has been well recognized.

Carvedilol prevents functional deficits in peripheral nerve mitochondria of rats with oxaliplatin-evoked painful peripheral neuropathy.

Oxaliplatin use as chemotherapeutic agent is frequently limited by cumulative neurotoxicity which may compromise quality of life. Reports relate this neurotoxic effect to oxidative stress and mitochondrial dysfunction in peripheral nerves and dorsal root ganglion (DRG). Carvedilol is an antihypertensive drug, has also been appreciated for its antioxidant and mitoprotective properties.

Melatonin prevents mitochondrial dysfunction and promotes neuroprotection by inducing autophagy during oxaliplatin-evoked peripheral neuropathy.

Oxaliplatin, an organoplatinum compound, is used in the treatment of colorectal cancer, but its clinical use can be limited due to the development of peripheral neuropathy. Whilst mitochondrial dysfunction has been implicated as a major pathomechanism for oxaliplatin-induced neurotoxicity, the prevention of autophagy may also aggravate neuronal cell death. Melatonin, a well-known mitoprotectant and autophagy inducer, was used to examine its neuroprotective role in oxaliplatin-induced peripheral neuropathy (OIPN).

Poly(ADP-ribose) polymerase inhibition reveals a potential mechanism to promote neuroprotection and treat neuropathic pain.

Neuropathic pain is triggered by the lesions to peripheral nerves which alter their structure and function. Neuroprotective approaches that limit the pathological changes and improve the behavioral outcome have been well explained in different experimental models of neuropathy but translation of such strategies to clinics has been disappointing. Experimental evidences revealed the role of free radicals, especially peroxynitrite after the nerve injury.

Combination strategy of PARP inhibitor with antioxidant prevent bioenergetic deficits and inflammatory changes in CCI-induced neuropathy.

Neuropathic pain, a debilitating pain condition and the underlying pathogenic mechanisms are complex and interwoven amongst each other and still there is scant information available regarding therapies which promise to treat the condition. Evidence indicate that oxidative/nitrosative stress induced poly (ADP-ribose) polymerase (PARP) overactivation initiate neuroinflammation and bioenergetic crisis culminating into neurodegenerative changes following nerve injury. Hence, we investigated the therapeutic effect of combining an antioxidant, quercetin and a PARP inhibitor, 4-amino 1, 8-naphthalimide (4-ANI) on the hallmark deficits induced by chronic constriction injury (CCI) of sciatic nerve in rats.

Morin Mitigates Chronic Constriction Injury (CCI)-Induced Peripheral Neuropathy by Inhibiting Oxidative Stress Induced PARP Over-Activation and Neuroinflammation.

Neuropathic pain is initiated or caused due to the primary lesion or dysfunction in the nervous system and is proposed to be linked to a cascade of events including excitotoxicity, oxidative stress, neuroinflammation and apoptosis. Oxidative/nitrosative stress aggravates the neuroinflammation and neurodegeneration through poly (ADP) ribose polymerase (PARP) overactivation. Hence, the present study investigated the antioxidant and anti-inflammatory effects of the phytoconstituent; morin in chronic constriction injury (CCI) induced neuropathy.

Adenosine Monophosphate-Activated Protein Kinase Abates Hyperglycaemia-Induced Neuronal Injury in Experimental Models of Diabetic Neuropathy: Effects on Mitochondrial Biogenesis, Autophagy and Neuroinflammation.

Impaired adenosine monophosphate kinase (AMPK) signalling under hyperglycaemic conditions is known to cause mitochondrial dysfunction in diabetic sensory neurons. Facilitation of AMPK signalling is previously reported to ameliorate inflammation and induce autophagic response in various complications related to diabetes. The present study assesses the role of AMPK activation on mitochondrial biogenesis, autophagy and neuroinflammation in experimental diabetic neuropathy (DN) using an AMPK activator (A769662).

PARP inhibition attenuates neuroinflammation and oxidative stress in chronic constriction injury induced peripheral neuropathy.

Aim: Peripheral nerve degeneration after nerve injury is accompanied with oxidative stress that may activate poly ADP-ribose polymerase (PARP, DNA repair enzyme). PARP overactivation amplifies the neuronal damage either due to energy crisis or through inflammatory process by facilitating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Hence investigated the role of PARP inhibitors, 3-Aminobenzamide (3-AB) and 1,5-isoquinolinediol (ISO) in the attenuation of chronic constriction injury (CCI) induced peripheral neuropathy in rats.

Potential Therapeutic Benefits of Maintaining Mitochondrial Health in Peripheral Neuropathies.

Background: Peripheral neuropathies are a group of diseases characterized by malfunctioning of peripheral nervous system. Neuropathic pain, one of the core manifestations of peripheral neuropathy remains as the most severe disabling condition affecting the social and daily routine life of patients suffering from peripheral neuropathy.

Method: The current review is aimed at unfolding the possible role of mitochondrial dysfunction in peripheral nerve damage and to discuss on the probable therapeutic strategies against neuronal mitotoxicity.

Fisetin Imparts Neuroprotection in Experimental Diabetic Neuropathy by Modulating Nrf2 and NF-κB Pathways.

The current study is aimed to assess the therapeutic potential of fisetin, a phytoflavonoid in streptozotocin (STZ)-induced experimental diabetic neuropathy (DN) in rats. Fisetin was administered (5 and 10 mg/kg) for 2 weeks (7th and 8th week) post STZ administration. Thermal and mechanical hyperalgesia were assessed by measuring tactile sensitivity to thermal and mechanical stimuli, respectively.

Boswellia ovalifoliolata abrogates ROS mediated NF-κB activation, causes apoptosis and chemosensitization in Triple Negative Breast Cancer cells.

The present study was aimed to evaluvate the apoptogenic potential of ethanolic extract of leaves from Boswellia ovalifoliolata (BL EthOH) and to unravel the molecular mechanisms implicated in apoptosis of Triple Negative Breast Cancer (TNBC) cells. BL EthOH was cytotoxic against TNBC cells like MDA-MB-231 and MDA-MB-453 with IC₅₀ concentrations 67.48 ± 5.

Neuroinflammation and oxidative stress in diabetic neuropathy: futuristic strategies based on these targets.

In Diabetes, the chronic hyperglycemia and associated complications affecting peripheral nerves are one of the most commonly occurring microvascular complications with an overall prevalence of 50-60%. Among the vascular complications of diabetes, diabetic neuropathy is the most painful and disabling, fatal complication affecting the quality of life in patients. Several theories of etiologies surfaced down the lane, amongst which the oxidative stress mediated damage in neurons and surrounding glial cell has gained attention as one of the vital mechanisms in the pathogenesis of neuropathy.