Model Of Neuropathy Research Articles

Deficiency of KIF15 contributes to oxaliplatin-induced cold hypersensitivity by limiting annexin A2 and enhancing TRPA1 localization in DRG neuronal membrane.

Effective treatments for oxaliplatin-induced cold hypersensitivity remain a significant clinical challenge, primarily due to gaps in our understanding of the underlying pathophysiology. Our previous studies have indicated that kinesin-12 (KIF15) is expressed in neurons, suggesting its potential involvement in neurodevelopment and neuronal plasticity. However, its role in mediating chemotherapy-induced pain in primary sensory neurons has not yet been reported. In this study, we found that KIF15-knockout (Kif15-KO) mice showed an increase in cold sensitivity, with this heightened cold hypersensitivity being dependent on the accumulation of the TRP ankyrin 1 (TRPA1) channel on the cell membrane. We further demonstrated that in a model of oxaliplatin-induced peripheral neuropathy (OIPN), KIF15 expression was markedly reduced, coinciding with an increase in TRPA1 membrane localization and a physical interaction between KIF15 and Annexin A2 in peripheral sensory neurons. This suggests a mechanistic link where the loss of KIF15 disrupts the function of Annexin A2, enhancing the localization of TRPA1 on the cell membrane of dorsal root ganglion (DRG) neurons, thereby contributing to cold hypersensitivity. Our results offer a new understanding of the molecular mechanisms underlying chemotherapy-induced cold hypersensitivity, highlighting KIF15 as a key regulator and a potential therapeutic target for conditions like OIPN.

Upregulation of the neuropeptide receptor calcitonin receptor-like in the spinal cord via MLL2 in a mouse model of paclitaxel-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and severe side effect affecting cancer patients undergoing paclitaxel treatment. Growing evidence underscores the pivotal role of calcitonin-related peptide (CGRP) in the development of CIPN. Repeated administration of paclitaxel induces alterations in CGRP release from sensory neurons within the dorsal root ganglia (DRG). The density of the CGRP receptor is most prominent in the dorsal horn of the spinal cord, where it overlaps with the distribution of CGRP. However, the impact of chemotherapy treatment on expression of the CGRP receptor in the spinal cord remains unclear, as well as the potential therapeutic benefits of a CGRP receptor antagonist in an animal model of CIPN. Using a mouse model of paclitaxel-induced mechanical hypersensitivity, we show upregulation of Calcitonin receptor-like receptor (Calcrl) mRNA expression in the spinal cord, an event that occurred in association with upregulation of the H3K4 methyltransferase MLL2. This effect of repeated paclitaxel administration was also linked to an increase in the recruitment of MLL2, thereby enhancing levels of the active mark H3K4me2 at the Calcrl promoter. Furthermore, administration of the CGRP receptor antagonist BIBN4096 mitigated mechanical and cold hypersensitivity in paclitaxel-treated mice. Together, these observations suggest the CGRP receptor in the spinal cord as a potential target for reducing paclitaxel-induced neuropathic pain in animal models.

Targeting the insular cortex for neuropathic pain modulation: Insights into synaptic and neuronal mechanisms.

Neuropathic pain, caused by nerve damage, greatly affects quality of life. Recent research proposes modulating brain activity, particularly through electrical stimulation of the insular cortex (IC), as a treatment option. This study aimed to understand how IC stimulation (ICS) affects pain modulation. In a rat neuropathy model, researchers used optogenetic and ICS techniques to evaluate changes in mechanical allodynia and synaptic changes, focusing on glutamate receptors (AMPAR, NR2A, NR2B). Optogenetic inhibition of IC neurons relieved pain without altering synaptic plasticity. However, repetitive ICS combined with optogenetic activation diminished the pain-relieving effects of ICS and increased AMPAR and NR2B receptor levels. Additionally, activating inhibitory neurons also reduced pain, while repetitive activation of excitatory neurons lessened the effectiveness of ICS and was associated with heightened receptor expression. These findings suggest that inhibiting excitatory neurons or activating inhibitory neurons in the IC could help modulate pain in neuropathic conditions, shedding light on how ICS can influence pain management through changes in synaptic plasticity.

Investigation of the protective effects of dichloroacetic acid in a rat model of diabetic neuropathy

BackgroundDiabetic neuropathy (DN) is a heterogeneous condition characterized by complex pathophysiological changes affecting both autonomic and somatic components of the nervous system. Inflammation and oxidative stress are recognized contributors to the pathogenesis of DN. This study aims to evaluate the therapeutic potential of dichloroacetic acid (DCA) in alleviating DN symptoms, focusing on its anti-inflammatory and antioxidant properties.MethodsThirty-two adult male Sprague Dawley rats were divided into four groups: Control, Diabetic, and two DCA-treated groups receiving 5 mg/kg and 10 mg/kg of DCA, respectively. Diabetes was induced with streptozotocin (STZ) injections. Assessments included lipid peroxidation levels, plasma fibroblast growth factor-21 (FGF-21) and transforming growth factor-beta (TGF-β) levels, electrophysiological measurements, histological examination of the sciatic nerve, and motor function tests.ResultsTreatment with DCA significantly reduced malondialdehyde (MDA) levels, indicating decreased lipid peroxidation. Plasma TGF-β levels were also lower in the DCA-treated groups, suggesting diminished inflammation. Conversely, plasma FGF-21 levels were elevated. Electrophysiological assessments revealed enhanced compound muscle action potential (CMAP) amplitudes and reduced distal latencies in DCA-treated rats, indicative of improved nerve conduction. Histopathological examinations showed reduced perineural thickness in the sciatic nerves of DCA-treated rats, pointing to decreased fibrosis. Enhanced performance in motor function tests was observed in these rats, implying improved muscle strength and motor capacity.ConclusionsThe study demonstrates that DCA therapy significantly reduces oxidative stress and inflammation in a rat model of DN, thereby ameliorating neuropathic symptoms. These results support the potential of DCA as a promising therapeutic agent for DN treatment. Further research is warranted to explore its clinical applications and to provide more detailed insights.

Phenylalanine-derived β-lactam TRPM8 antagonists: revisiting configuration and new benzoyl derivatives

Aim: To expand the understanding of the structure-activity relationship within a family of amino acid-derived β-lactam TRPM8 (transient receptor potential melastatin channel, subtype 8) antagonists, this work investigated both the configuration-dependence of potency and selectivity, and explored strategies for increasing total polar surface area (TPSA). Methods: Diastereoisomeric compounds derived from H-Phe-OtBu, and analogues incorporating differently substituted benzoyl groups, were synthesized by stereoselective solution pathways. Ca2+ microfluorometry assays were used for TRPM8 antagonist activity assessment, and then confirmed through electrophysiology (patch-clamp assay). The pharmacological activity in vivo was studied on a mice model of oxaliplatin-induced peripheral neuropathy. Results: For OtBu derivatives, a 3S,4S-configuration was preferred, while compounds with 2'R chiral centers show higher selectivity for TRPM8 versus transient receptor potential vanilloid, subtype 1 (TRPV1) than their 2'S-counterparts. N-terminal benzoyl derivatives, which increased TPSA values, resulted in equipotent compounds as previous prototypes, but also showed activity in other pain-related targets [TRPV1 and cannabinoid receptor, subtype 2 (CB2R)]. A selected N-benzoyl derivative displays antinociceptive activity in vivo. Conclusions: The potency and selectivity of these β-lactam TRPM8 antagonists developed from amino acid derivatives depend not only on the configuration but also on the substituents at the 4-carboxy and at the N-benzoyl groups. Dual and multitarget compounds were discovered within this family of TRPM8 antagonists.

Increased TRPA1 functionality in the skin of rats and cancer patients following oxaliplatin treatment.

Chemotherapy-induced peripheral neuropathy is a debilitating pathology affecting a majority of patients who are being treated with specific cytostatic compounds including oxaliplatin. Various in vitro, ex vivo and in vivo preclinical experiments indicate that transient receptor potential ankyrin 1 (TRPA1) plays a crucial role in the symptomatology of chemotherapy-induced peripheral neuropathy. However, it is unclear whether oxaliplatin also modulates the TRPA1 functionality in the skin of rodents or patients. Here, we quantified the vasodilation after topical application of the TRPA1 agonist cinnamaldehyde in a rodent model of chemotherapy-induced peripheral neuropathy (male Sprague Dawley rats, aged 6 weeks) as well as on fingers of patients suffering from chronic chemotherapy-induced peripheral neuropathy after oxaliplatin treatment. Compared to vehicle-treated rats, a cumulative dose of oxaliplatin 32 mg/kg enhanced the vasodilation after cinnamaldehyde application on rat abdominal skin. Likewise, also in patients with chronic chemotherapy-induced peripheral neuropathy after oxaliplatin, the response to cinnamaldehyde was significantly higher compared to sex- and age-matched healthy controls. Thereby, this study is the first to translate the evidence of increased TRPA1 functionality in vitro or ex vivo in rodents to in vivo conditions in human. The increased TRPA1 functionality in patients with chronic chemotherapy-induced peripheral neuropathy does not only confirm the potential of TRPA1 as target to hit to provide efficacious analgesia, it also paves the way for additional patient stratification on a molecular level and possible treatment response prediction.

Torsion-Induced Traumatic Optic Neuropathy (TITON): A physiologically relevant animal model of traumatic optic neuropathy.

Traumatic optic neuropathy (TON) is a common cause of irreversible blindness following head injury. TON is characterized by axon damage in the optic nerve followed by retinal ganglion cell death in the days and weeks following injury. At present, no therapeutic or surgical approach has been found to offer any benefit beyond observation alone. This is due in part to the lack of translational animal models suitable for understanding mechanisms and evaluating candidate treatments. In this study, we developed a rat model of TON in which the eye is rapidly rotated, inflicting mechanical stress on the optic nerve and leading to significant visual deficits. These functional deficits were thoroughly characterized up to one week after injury using electrophysiology and immunohistochemistry. The photopic negative response (PhNR) of the light adapted full field electroretinogram (LA ffERG) was significantly altered following injury. This correlated with increased biomarkers of retinal stress, axon disruption, and cell death. Together, this evidence suggests the utility of our model for mimicking clinically relevant TON and that the PhNR may be an early diagnostic for TON. Future studies will utilize this animal model for evaluation of candidate treatments.

TET1 participates in oxaliplatin-induced neuropathic pain by regulating microRNA-30b/Nav1.6.

Chemotherapy-induced neuropathic pain poses significant clinical challenges and severely impacts patient quality of life. Sodium ion channels are crucial in regulating neuronal excitability and pain. Our research indicates that the microRNA-30b (miR-30b) in rat dorsal root ganglia (DRG) contributes to chemotherapy-induced neuropathic pain by regulating the Nav1.6 protein. Additionally, Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) plays a crucial role in pain generation by altering gene expression. We established a chemotherapy-induced neuropathy model using intraperitoneal Oxaliplatin (OXA) injections and measured TET1 and Nav1.6 protein in the DRG. Using lentivirus and Tet1flox/flox mice, we modulated TET1 expression and assessed pain behaviors, DRG neuronal excitability, Nav1.6 currents, miR-30b-5p, and demethylation of the Mir30b promoter region. We employed Chromatin immunoprecipitation (CHIP) to pinpoint TET1 binding sites on the Mir30b promoter. The impacts of miR-30b agomir or antagomir on Nav1.6 expression and pain responses were assessed post-intrathecal injections. The results showed that OXA reduced TET1, increasing neuronal excitability, Nav1.6 currents, and miR-30b-5p in the DRG. TET1 knockdown exacerbated these effects and induced pain behaviors. Conversely, TET1 overexpression reversed these effects. TET1 also targeted and enhanced demethylation at the Mir30b promoter (-1103 bp to -1079 bp). miR-30b agomir reduces Nav1.6, whereas miR-30b antagomir reverses TET1's effects on Nav1.6 and pain. In OXA-induced neuropathy, decreased TET1 reduces miR-30b, elevating Nav1.6 expression and currents, and contributing to pain. We hypothesize that TET1 mediates this process by regulating the demethylation of the Mir30b promoter.

Refining Flash Visual Evoked Potential Analysis in Rats: A Novel Approach Using Bilateral Epidural Electrodes.

Visual evoked potentials (VEPs) are electrical signals generated at the visual cortex following visual stimulation. Flash VEPs (fVEPs) are produced by global retinal stimulation and are considered an objective measure of the integrity of the entire visual pathway. However, fVEP measurements are highly sensitive to external variables, making relative comparisons of the fVEP waveforms between the two eyes in the same individual challenging. We used the rodent non-arteritic anterior ischemic optic neuropathy (rNAION) model to induce unilateral ischemic optic neuropathy. The severity of optic disc edema was measured with spectral-domain optical coherence tomography, and visual acuity was measured using a virtual optokinetic system. We developed a procedure utilizing implanted bilateral epidural electrodes and derived a mathematical formula to accurately estimate functional differences between the optic nerves. Immunohistology was performed to quantify retinal ganglion cell (RGC) survival using stereology. Compared to subcutaneous methods, the new approach significantly improves the signal-to-noise ratio and is more repeatable when comparing the two eyes. The derived formula accounts for asymmetry in the afferent inputs to the visual cortex. Visual function calculated using the formula correlates strongly with other recognized metrics of visual function, including RGC survival and visual acuity. We have developed a repeatable and accurate method to calculate the relative visual function of diseased optic nerves compared with a contralateral control eye. Our novel method improves fVEP measurement sensitivity and accuracy in rodent preclinical trials, reducing the number of animals needed to achieve statistical significance.

Astaxanthin has a beneficial influence on pain-related symptoms and opioid-induced hyperalgesia in mice with diabetic neuropathy-evidence from behavioral studies

BackgroundThe treatment of painful diabetic neuropathy is still a clinical problem. The aim of this study was to determine whether astaxanthin, a substance that inhibits mitogen-activated protein kinases, activates nuclear factor erythroid 2-related factor 2 and influences N-methyl-D-aspartate receptor, affects nociceptive transmission in mice with diabetic neuropathy.MethodsThe studies were performed on streptozotocin-induced mouse diabetic neuropathic pain model. Single intrathecal and intraperitoneal administrations of astaxanthin at various doses were conducted in both males and females. Additionally, repeated twice-daily treatment with astaxanthin (25 mg/kg) and morphine (30 mg/kg) were performed. Hypersensitivity was evaluated with von Frey and cold plate tests.ResultsThis behavioral study provides the first evidence that in a mouse model of diabetic neuropathy, single injections of astaxanthin similarly reduce tactile and thermal hypersensitivity in both male and female mice, regardless of the route of administration. Moreover, repeated administration of astaxanthin slightly delays the development of morphine tolerance and significantly suppresses the occurrence of opioid-induced hyperalgesia, although it does not affect blood glucose levels, body weight, or motor coordination. Surprisingly, astaxanthin administered repeatedly produces a better analgesic effect when administered alone than in combination with morphine, and its potency becomes even more pronounced over time.ConclusionsThese behavioral results provide a basis for further evaluation of the potential use of astaxanthin in the clinical treatment of diabetic neuropathy and suggest that the multidirectional action of this substance may have positive effects on relieving neuropathic pain in diabetes.

Neuroprotective potential of Alpinia calcarata and HPLC analysis of stigmasterol against cisplatin-induced neuropathy in rat model

Cisplatin is a chemotherapeutic agent known for causing severe peripheral neuropathy as a side effect, impacting patients’ quality of life by damaging nerve tissues. This study aims to explore the neuroprotective effects of the ethanolic extract of Alpinia calcarata Roscoe rhizome (EEACR) and stigmasterol identified by high-performance liquid chromatography (HPLC) in a rat model of cisplatin-induced neuropathy. Male Wistar rats were divided into control, cisplatin-induced neuropathic, and two intervention groups receiving different concentrations of EEACR (250 and 500 mg/kg). Neuropathy was induced with cisplatin administered intraperitoneally at a dose of 2 mg/kg per week for five weeks. The intervention groups were treated orally with EEACR daily during the induction period. Treatment with EEACR showed a significant attenuation of neurotoxicity as evidenced by behavioural improvements in mechanical allodynia, thermal hyperalgesia, and cold allodynia. HPLC analysis confirmed the presence of stigmasterol in EEACR, which may contribute to its therapeutic effects. Biochemical assessments revealed a significant decrease in oxidative stress markers and an increase in antioxidant enzyme activities, including superoxide dismutase, catalase, and glutathione peroxidase, in the nervous tissues of EEACR-treated rats. Histopathological examination indicated a reduction in nerve damage and enhanced preservation of myelin and axonal structures in the treatment groups. The findings from this study suggest that EEACR, enriched with stigmasterol, offers promising neuroprotective effects against cisplatin-induced neuropathy in rats.

Hypoxia-mediated rescue of retinal ganglion cells deficient in mitochondrial complex I is independent of the hypoxia-inducible factor pathway

Continuous exposure to environmental hypoxia (11% O2) has been shown to markedly slow the progressive degeneration of retinal ganglion cells (RGCs) in a mouse model of mitochondrial optic neuropathy with RGC-specific deletion of the key mitochondrial complex I accessory subunit ndufs4. As a first step toward identifying the therapeutic mechanism of hypoxia in this model, we conducted a series of experiments to investigate the role of the hypoxia-inducible factor (HIF) regulatory pathway in RGC neuroprotection. Vglut2-Cre; ndufs4loxP/loxP mice were crossed with strains bearing floxed alleles of the negative HIF regulatory vhl or of the two major HIF α-subunit isoforms, Hif1α and Hif2α. Deletion of vhl within ndufs4-deficient RGCs failed to prevent RGC degeneration under normoxia, indicating that HIF activation is not sufficient to achieve RGC rescue. Furthermore, the rescue of ndufs4-deficient RGCs by hypoxia remained robust despite genetic inactivation of Hif1α and Hif2α. Our findings demonstrate that the HIF pathway is entirely dispensable to the rescue of RGCs by hypoxia. Future efforts to uncover key HIF-independent molecular pathways induced by hypoxia in this mouse model may be of therapeutic relevance to mitochondrial optic neuropathies such as Leber hereditary optic neuropathy.

Torsion-Induced Traumatic Optic Neuropathy (TITON): A Physiologically Relevant Animal Model of Traumatic Optic Neuropathy.

Traumatic optic neuropathy (TON) is a common cause of irreversible blindness following head injury. TON is characterized by axon damage in the optic nerve followed by retinal ganglion cell death in the days and weeks following injury. At present, no therapeutic or surgical approach has been found to offer any benefit beyond observation alone. This is due in part to the lack of translational animal models suitable for understanding mechanisms and evaluating candidate treatments. In this study, we developed a rat model of TON in which the eye is rapidly rotated, inflicting mechanical stress on the optic nerve and leading to significant visual deficits. These functional deficits were thoroughly characterized up to one week after injury using electrophysiology and immunohistochemistry. The photopic negative response (PhNR) of the light adapted full field electroretinogram (LA ffERG) was significantly altered following injury. This correlated with increased biomarkers of retinal stress, axon disruption, and ganglion cell death. Together, this evidence suggests the utility of our model for mimicking clinically relevant TON and that the PhNR may be an early diagnostic for TON. We also found indirect evidence that ketamine, which was used for anesthesia, may ameliorate TON. Future studies will utilize this animal model for evaluation of candidate treatments.

The effectivity of emulgel from ethanolic extract of cocoa pod husk in mice model of painful diabetic neuropathy

Painful diabetic neuropathy (PDN) is nerve damage caused by the accumulation of oxidative stress. Resveratrol, an antioxidant compound found in various plants, including cocoa pod husk, combats this condition. To prove the efficacy of an emulgel from an ethanolic extract of cocoa pod husk in PDN mice. The cocoa husk ethanol extract was formulated into emulgel and evaluated. Dermal sensitization reactions and a dermal acute toxicity test were conducted. In the PDN model, mice were induced using alloxan 225 mg/kg BW i. p. After 14 days, mice were randomized into eight groups: Normal, diabetic, 0.1% capsaicin cream, and cocoa pod husk extract emulgel (CPHEE) (0.25%, 0.5%, 1%, 2%, and 3%). Treatment was given three times a day for 14 days. Latency time and blood glucose levels were observed every week. Plantar skin sections were stained with h and e for histological observation and the transient receptor protein vanilloid (TRPV)-1 for immunohistochemistry. In vivo tests showed that a 2% dose of CPHEE improved hyperalgesia by 92.33% ±1.52%, improved histology, and minimized the expression of TRPV-1 in the skin, same as capsaicin 0.1%. Notably, up to a dose of 2000 mg/kg, CPHEE did not show toxic symptoms in mice or erythema and edema, further confirming its safety for use in PDN. The study confirms that a 2% CPHEE is effective and safe for topical use in PDN, providing a potential solution for patients suffering from this condition.

Exploring clinical markers of Axon degeneration processes in Chemotherapy-induced peripheral neuropathy among young adults receiving vincristine or paclitaxel.

Approximately 70% of patients receiving neurotoxic chemotherapy (e.g., paclitaxel or vincristine) will develop chemotherapy-induced peripheral neuropathy. Despite the known negative effects of CIPN on physical functioning and chemotherapy dosing, little is known about how to prevent CIPN. The development of efficacious CIPN prevention interventions is hindered by the lack of knowledge surrounding CIPN mechanisms. Nicotinamide adenine dinucleotide (NAD+) and cyclic-adenosine diphosphate ribose (cADPR) are potential markers of axon degeneration following neurotoxic chemotherapy, however, such markers have been exclusively measured in preclinical models of chemotherapy-induced peripheral neuropathy (CIPN). The overall objective of this longitudinal, observational study was to determine the association between plasma NAD+, cADPR, and ADPR with CIPN severity in young adults receiving vincristine or paclitaxel. Young adults (18-39 years old) beginning vincristine or paclitaxel were recruited from Dana-Farber Cancer Institute. Young adults completed the QLQ-CIPN20 sensory and motor subscales and provided a blood sample prior to starting chemotherapy (T1) and at increasing cumulative vincristine (T2: 3-5mg, T3: 7-9mg) and paclitaxel (T2: 300-500 mg/m2, T3: 700-900 mg/m2) dosages. NAD+, cADPR, and ADPR were quantified from plasma using mass spectrometry. Metabolite levels and QLQ-CIPN20 scores over time were compared using mixed-effects linear regression models and/or paired two-sample tests. Participants (N = 50) were mainly female (88%), white (80%), and receiving paclitaxel (78%). Sensory and motor CIPN severity increased from T1-T3 (p < 0.001). NAD+ (p = 0.28), cADPR (p = 0.62), and ADPR (p = 0.005) values decreased, while cADPR/NAD+ ratio increased from T1-T3 (p = 0.50). There were no statistically significant associations between NAD + and QLQ-CIPN20 scores over time. To our knowledge, this is the first study to measure plasma NAD+, cADPR, and ADPR among patients receiving neurotoxic chemotherapy. Although, no meaningful changes in NAD+, cADPR, or cADPR/NAD+ were observed among young adults receiving paclitaxel or vincristine. Future research in an adequately powered sample is needed to explore the clinical utility of biomarkers of axon degeneration among patients receiving neurotoxic chemotherapy to guide mechanistic research and novel CIPN treatments.

Proteomic analysis of dorsal root ganglia in a mouse model of paclitaxel-induced neuropathic pain.

Paclitaxel is a chemotherapy drug widely used for the treatment of various cancers based on its ability to potently stabilize cellular microtubules and block division in cancer cells. Paclitaxel-based treatment, however, accumulates in peripheral system sensory neurons and leads to a high incidence rate (over 50%) of chemotherapy induced peripheral neuropathy in patients. Using an established preclinical model of paclitaxel-induced peripheral neuropathy (PIPN), we examined proteomic changes in dorsal root ganglia (DRG) of adult male mice that were treated with paclitaxel (8 mg/kg, at 4 injections every other day) relative to vehicle-treated mice. High throughput proteomics based on liquid chromatography electrospray ionization mass spectrometry identified 165 significantly altered proteins in lumbar DRG. Gene ontology enrichment and bioinformatic analysis revealed an effect of paclitaxel on pathways for mitochondrial regulation, axonal function, and inflammatory purinergic signaling as well as microtubule activity. These findings provide insight into molecular mechanisms that can contribute to PIPN in patients.

Indirect involvement of α2-adrenoceptors in the mechanical antihypersensitivity effect induced by the spinally administered imidazoline I1 receptor ligand LNP599 in a rat model of experimental neuropathy

Here we assess whether neuropathic pain hypersensitivity is attenuated by spinal administration of the imidazoline I1-receptor agonist LNP599 and whether the attenuation involves co-activation of α2-adrenoceptors. Spared nerve injury (SNI) model of neuropathy was used to induce mechanical hypersensitivity in male and female rats with a chronic catheter for intrathecal drug administrations. Mechanical sensitivity and heat nociception were assessed behaviorally in the injured limb. Additionally, GTPγS radioligand binding assay, β-arrestin recruitment and intracellular cAMP levels were used for receptor profiling in vitro. LNP599 (imidazoline I1 receptor agonist) and clonidine (α2-adrenoceptor agonist) produced equal dose-related mechanical antihypersensitivity effects in both sexes. LNP599 attenuated heat nociception preferentially in males, while clonidine reduced heat nociception equally in males and females. Carbophenyline (another imidazoline I1 receptor agonist) had no significant effect on mechanical hypersensitivity or heat nociception in males or females. Mechanical antihypersensitivity and heat antinociception induced by LNP599 in SNI males was prevented by pretreatments with yohimbine or atipamezole (two α2-adrenoceptor antagonists) but not by efaroxan (a mixed imidazoline I1 receptor/α2-adrenoceptor antagonist). In vitro assays indicated that LNP599 does not activate α2A- or other subtypes of α2-adrenoceptors. However, LNP599 was a weak partial agonist for 5-HT2B receptors and bound to sigma-1 and sigma-2 receptors that all are involved in modulation of spinal nociception. The results indicate that the suppression of neuropathic pain hypersensitivity by LNP599 is not due to action on spinal imidazoline I1 receptors, but rather due to indirect activation of spinal α2-adrenoceptors.

Harmaline attenuates chemotherapy-induced peripheral neuropathy: Modulation of Nrf-2 pathway and NK-1 receptor signaling

Peripheral neuropathy, resulting from damage to peripheral nerves, manifests as weakness, numbness, and pain, primarily affecting extremities and significantly impairing quality of life, especially in the elderly. Current treatments often entail severe side effects, necessitating the exploration of alternative therapies. Harmaline, a β-carboline alkaloid derived from Peganum harmala, exhibits promising antioxidant and anti-inflammatory properties. This study aimed to assess the efficacy of harmaline in a vincristine-induced mouse model of peripheral neuropathy. Swiss albino mice received vincristine (0.1 mg/kg, i.p.) for 10 days to induce neuropathy. Harmaline (5 and 10 mg/kg, i.p.) was administered 30 min before vincristine and continued until day 14 to evaluate its protective effects. Behavioral assessments were conducted on days 7 and 14. Vincristine treatment significantly heightened sensitivity to cold, measured by cold plate and acetone drop tests, and to heat, assessed via the hot plate test, while also impairing motor coordination. Biochemical analyses revealed decreased levels of GSH and Nrf-2, alongside elevated TBARS and IL-1β levels in sciatic nerve tissue. Harmaline administration markedly alleviated both behavioral and biochemical alterations induced by vincristine, with the 10 mg/kg dose exhibiting the most pronounced effects. Notably, harmaline treatment elevated GSH and Nrf-2 levels while reducing TBARS and IL-1β. Furthermore, substance-P treatment reversed the protective effects of harmaline, implicating the NK-1 receptor in its mechanism of action. In conclusion, harmaline demonstrates significant potential in mitigating vincristine-induced peripheral neuropathy by reducing oxidative stress through Nrf-2 activation and lowering IL-1β levels, likely via NK-1 receptor inhibition.

Retinal damage promotes mitochondrial transfer in the visual system of a mouse model of Leber hereditary optic neuropathy

Lenadogene nolparvovec is a gene therapy which has been developed to treat Leber hereditary optic neuropathy (LHON) caused by a point mutation in the mitochondrial NADH dehydrogenase 4 (ND4) gene. Clinical trials have demonstrated a significant improvement of visual acuity up to 5 years after treatment by lenadogene nolparvovec but, surprisingly, unilateral treatment resulted in bilateral improvement of vision. This contralateral effect – similarly observed with other gene therapy products in development for MT-ND4-LHON – is supported by the migration of viral vector genomes and their transcripts to the contralateral eye, as reported in animals, and post-mortem samples from two patients. In this study, we used an AAV2 encoding fluorescent proteins targeting mitochondria to investigate whether these organelles themselves could transfer from the treated eye to the fellow one. We found that mitochondria travel along the visual system (optic chiasm and primary visual cortex) and reach the contralateral eye (optic nerve and retina) in physiological conditions. We also observed that, in a rotenone-induced model of retinal damage mimicking LHON, mitochondrial transfer from the healthy to the damaged eye was accelerated and enhanced. Our results thus provide a further explanation for the contralateral beneficial effect observed during clinical studies with lenadogene nolparvovec.

Platinum Deposition in the Central Nervous System: A Novel Insight into Oxaliplatin-induced Peripheral Neuropathy in Young and Old Mice.

Numerous factors can contribute to the incidence or exacerbation of peripheral neuropathy induced by oxaliplatin (OXA). Recently, platinum accumulation in the spinal cord of mice after OXA exposure, despite the efficient defenses of the central nervous system, has been demonstrated by our research group, expanding the knowledge about its toxicity. One hypothesis is platinum accumulation in the spinal cord causes oxidative damage to neurons and impairs mitochondrial function. Thus, the main aim of this study was to investigate the relationship between aging and OXA-induced neuropathic pain and its comorbidities, including anxious behavior and cognitive impairment. By using an OXA-induced peripheral neuropathy model, platinum and bioelement concentrations and their influence on oxidative damage, neuroprotection, and neuroplasticity pathways were evaluated in Swiss mice, and our findings showed that treatment with OXA exacerbated pain and anxious behavior, albeit not age-induced cognitive impairment. Platinum deposition in the spinal cord and, for the first time, in the brain of mice exposed to OXA, regardless of age, was identified. We found that alterations in bioelement concentration, oxidative damage, neuroprotection, and neuroplasticity pathways induced by aging contribute to OXA-induced peripheral neuropathy. Our results strive to supply a basis for therapeutic interventions for OXA-induced peripheral neuropathy considering age specificities.