Effect of weak, interrupted sinusoidal low frequency magnetic field on neural regeneration in rats: functional evaluation

A study of the effect of weak, interrupted sinusoidal low frequency magnetic field (ISMF) stimulation on regeneration of the rat sciatic nerve was carried out. In the experiment, 60 Wistar rats were used: 24 rats underwent unilateral sciatic nerve transection injury and immediate surgical nerve repair, 24 rats underwent unilateral sciatic nerve crush injury, and the remaining 12 rats underwent a sham surgery. Half of the animals (n = 12) with either sciatic nerve lesion were randomly chosen and exposed between a pair of Helmholtz coils for 3 weeks post-injury, 4 h/day, to an interrupted (active period to pause ratio = 1.4 s/0.8 s) sinusoidal 50 Hz magnetic field of 0.5 mT. The other half of the animals (n = 12) and six rats with sham surgery were used for two separate controls. Functional recovery was followed for 6 weeks for the crush injuries and 7(1/2) months for the transection injuries by video assisted footprint analysis in static conditions and quantified using a recently revised static sciatic index (SSI) formula. We ascertained that the magnetic field influence was weak, but certainly detectable in both injury models. The accuracy of ISMF influence detection, determined by the one-way repeated measures ANOVA test, was better for the crush injury model: F(1, 198) = 9.0144, P = .003, than for the transection injury model: F(1, 198) = 6.4826, P = .012. The Student-Newman-Keuls range test for each response day yielded significant differences (P < .05) between the exposed and control groups early in the beginning of functional recovery and later on from the points adjacent to the beginning of the plateau, or 95% of functional recovery, and the end of observation. These differences probably reflect the ISMF systemic effect on the neuron cell bodies and increased and more efficient reinnervation of the periphery.     

Variable spatial magnetic field influences peripheral nerves regeneration in rats

Generator of spatial magnetic field is one of most recent achievements among the magnetostimulators. This apparatus allows to obtain the rotating magnetic field. This new method may be more effective than other widely used techniques of magnetostimulation and magnetotherapy. We investigated the influence of alternating, spatial magnetic field on the regeneration of the crushed rat sciatic nerves. Functional and morphological evaluations were used. After crush injury of the right sciatic nerve, Wistar C rats (n?=?80) were randomly divided into four groups (control and three experimental). The experimental groups (A, B, C) were exposed (20?min/day, 5?d/week, 4 weeks) to alternating spatial magnetic field of three different intensities. Sciatic Functional Index (SFI) and tensometric assessments were performed every week after nerve crush. Forty-eight hours before the sacrificing of animals, DiI (1,1’-di-octadecyl-3,3,3’,3’-tetramethyloindocarbocyanine perchlorate) was applied 5?mm distally to the crush site. Collected nerves and dorsal root ganglia (DRG) were subjected to histological and immunohistochemical staining. The survival rate of DRG neurons was estimated. Regrowth and myelination of the nerves was examined. The results of SFI and tensometric assessment showed improvement in all experimental groups as compared to control, with best outcome observed in group C, exposed to the strongest magnetic field. In addition, DRG survival rate and nerve regeneration intensity were significantly higher in the C group. Above results indicate that strong spatial alternating magnetic field exerts positive effect on peripheral nerve regeneration and its application could be taken under consideration in the therapy of injured peripheral nerves.     

Lentiviral-mediated transfer of CDNF promotes nerve regeneration and functional recovery after sciatic nerve injury in adult rats

Peripheral nerve injury is often followed by incomplete and unsatisfactory functional recovery and may be associated with sensory and motor impairment of the affected limb. Therefore, a novel method is needed to improve the speed of recovery and the final functional outcome after peripheral nerve injuries. This report investigates the effect of lentiviral-mediated transfer of conserved dopamine neurotrophic factor (CDNF) on regeneration of the rat peripheral nerve in a transection model in vivo. We observed notable overexpression of CDNF protein in the distal sciatic nerve after recombinant CDNF lentiviral vector application. We evaluated sciatic nerve regeneration after surgery using light and electron microscopy and the functional recovery using the sciatic functional index and target muscle weight. HE staining revealed better ordered structured in the CDNF-treated group at 8 weeks post-surgery. Quantitative analysis of immunohistochemistry of NF200 and S-100 in the CDNF group revealed significant improvement of axonal and Schwann cell regeneration compared with the control groups at 4 weeks and 8 weeks after injury. The thickness of the myelination around the axons in the CDNF group was significantly higher than in the control groups at 8 weeks post-surgery. The CDNF group displayed higher muscle weights and significantly increased sciatic nerve index values. Our findings suggest that CDNF gene therapy could provide durable and stable CDNF protein concentration and has the potential to enhance peripheral nerve regeneration, morphological and functional recovery following nerve injury, which suggests a promising strategy for peripheral nerve repair.     

Spatiotemporal Expression of PSD-95 and nNOS After Rat Sciatic Nerve Injury

Neuronal nitric oxide synthase (nNOS) has been implicated to influence peripheral nerve lesion and regeneration. Post-synaptic density-95 (PSD-95) is one of nNOS-anchoring proteins and plays an important role in specifying the sites of reaction of NO in nervous system. Here we established a rat sciatic nerve crush (SNC) model to examine the spatiotemporal expression of PSD-95 and nNOS. At gene levels, PSD-95 mRNA diminished shortly after crush, and significantly elevated from 2 days to 2 weeks, whereas nNOS decreased progressively post-operation, reached the valley at 1 day, and markedly up-regulated from 1 to 2 weeks after SNC. The expression of both molecules returned to the control level at 4 weeks post-injury. At protein levels, PSD-95 and nNOS underwent the similar changes as their gene expression except for a time lag during up-regulating. At their peak expression, PSD-95 co-labeled with nNOS in Schwann cells (SCs) of sciatic nerve within 0.5 mm from the lesion site, but had few colocalization in axons. In addition, the interaction between PSD-95 and nNOS enhanced significantly at 2 weeks after SNC. These results suggest a correlation of PSD-95 up-regulation with nNOS in reactive SCs of crushed sciatic nerve, which may lead to understanding the function of PSD-95 during peripheral nerve regeneration. Shangfeng Gao and Min Fei contributed equally to this work.     

Non-thermal plasma application enhances the recovery of transected sciatic nerves in rats

This experimental research aimed to investigate the effects of non-thermal plasma on nerve regeneration after transected nerve damage using the sciatic nerve in Wistar albino (A) rats. The experiments were performed on 27 Wistar A rats. The rats underwent surgery for right sciatic nerve exposure and were divided into three groups (each group, n = 9) according to sciatic nerve transected injury (SNTI) and non-thermal plasma application: a non-nerve damage (non-ND) group, a only nerve damage without non-thermal plasma application (ND) group, and a nerve damage with non-thermal plasma application (ND + NTP) group. Subsequent to SNTI and immediate suture, non-thermal plasma was administered three times per week for eight weeks. Evaluation for functional recovery was performed using the static sciatic index measured over the full treatment period of eight weeks. The sciatic nerve specimens were obtained after euthanasia and third day from the last non-thermal plasma application. The sciatic nerve tissues were subjected to histological analysis. Behavior analysis presented that the ND + NTP group showed improved static sciatic index compared with the nerve damage group. Histopathological findings demonstrated that the ND + NTP group had more dense Schwann cells and well-established continuity of nerve fibers, greater than the nerve damage group. Immunohistochemistry showed that the ND + NTP group had increased levels of markers for microtubule-associated protein 2 (MAP2), tau, S100 calcium-binding protein B, and neurofilament-200 and regulated the overexpression of CD68 and MAP2. These results indicated that non-thermal plasma enhanced the motor function and restored the neuronal structure by accelerating myelination and axonal regeneration. Additionally, non-thermal plasma was confirmed to have a positive effect on the recovery of SNTI in rats.     

Beneficial Effect of Metformin on Nerve Regeneration and Functional Recovery After Sciatic Nerve Crush Injury in Diabetic Rats

Neuroprotective effects of metformin have been increasingly recognized in both diabetic and non-diabetic conditions. Thus far, no information has been available on the potential beneficial effects of metformin on peripheral nerve regeneration in diabetes mellitus. The present study was designed to investigate such a possibility. Diabetes was established by a single injection of streptozotocin at 50 mg/kg in rats. After sciatic nerve crush injury, the diabetic rats were intraperitoneally administrated daily for 4 weeks with metformin (30, 200 and 500 mg/kg), or normal saline, respectively. The axonal regeneration was investigated by morphometric analysis and retrograde labeling. The functional recovery was evaluated by electrophysiological studies and behavioral analysis. It was found that metformin significantly enhanced axonal regeneration and functional recovery compared to saline after sciatic nerve injury in diabetic rats. In addition, metformin at 200 and 500 mg/kg showed better performance than that at 30 mg/kg. Taken together, metformin is capable of promoting nerve regeneration after sciatic nerve injuries in diabetes mellitus, highlighting its therapeutic values for peripheral nerve injury repair in diabetes mellitus.     

Engineering a prokaryotic apocytochrome c as an efficient substrate for Saccharomyces cerevisiae cytochrome c heme lyase

In spite of the extensive research using induced pluripotent stem (iPS) cells, the therapeutic potential of iPS cells in the treatment of peripheral nerve injury is largely unknown. In this study, we repaired peripheral nerve gaps in mice using tissue-engineered bioabsorbable nerve conduits coated with iPS cell-derived neurospheres. The secondary neurospheres derived from mouse iPS cells were suspended in each conduit (4000,000 cells per conduit) and cultured in the conduit in three-dimensional (3D) culture for 14 days. We then implanted them in the mouse sciatic nerve gaps (5 mm) (iPS group; n=10). The nerve conduit alone was implanted in the control group (n=10). After 4, 8 and 12 weeks, motor and sensory functional recovery in mice were significantly better in the iPS group. At 12 weeks, all the nerve conduits remained structurally stable without any collapse and histological analysis indicated axonal regeneration in the nerve conduits of both groups. However, the iPS group showed significantly more vigorous axonal regeneration. The bioabsorbable nerve conduits created by 3D-culture of iPS cell-derived neurospheres promoted regeneration of peripheral nerves and functional recovery in vivo. The combination of iPS cell technology and bioabsorbable nerve conduits shows potential as a future tool for the treatment of peripheral nerve defects.     

Stimulation of the rat's sciatic nerve regeneration by local treatment with Xymedon

1. The possibility of a neuro-protective effect of Xymedon as a pharmacological stimulator of nerve regeneration has been studied through Schwann cells (SCs) located in the potential area of regenerating nerve fibers' growth. 2. Xymedon was injected into the silicone chamber connecting the central and peripheral stumps of the rat's sciatic nerve. Carboxymethyl cellulose was used as a depositioned medium. 3. A 0.95% concentration of Xymedon increased the sciatic nerve functional index (SFI) values on the 14th, 21st and 28th day after the operation. By day 30, the total number of survival neurons in the L5 dorsal root ganglion (DRG) on the ipsilateral side increased with the following changes in Xymedon concentration: [see text] The number of surviving sensory neurons in the group with 0.95% Xymedon increased by 36% (p < 0.05) compared with animals with depositioned medium but Xymedon free. 4. It is suggested that the positive effects of Xymedon on neural regeneration and recovery of motor function support the potential use of Xymedon for the treatment of peripheral nerve injuries.     

Electromagnetic field treatment of nerve crush injury in a rat model: effect of signal configuration on functional recovery

Electromagnetic fields (EMFs) have been demonstrated to enhance mammalian peripheral nerve regeneration in vitro and in vivo. Using an EMF signal shown to enhance neurite outgrowth in vitro, we tested this field in vivo using three different amplitudes. The rat sciatic nerve was crushed. Whole body exposure was performed for 4 h/day for 5 days in a 96-turn solenoid coil controlled by a signal generator and power amplifier. The induced electric field at the target tissue consisted of a bipolar rectangular pulse, having 1 and 0.3 ms durations in each polarity, respectively. Pulse repetition rate was 2 per second. By varying the current, the coils produced fields consisting of sham (no current) and peak magnetic fields of 0.03 mT, 0.3 mT, and 3 mT, corresponding to peak induced electric fields of 1, 10, and 100 microV/cm, respectively, at the tissue target. Walking function was assessed over 43 days using video recording and measurement of the 1-5 toe-spread, using an imaging program. Comparing injured to uninjured hind limbs, mean responses were evaluated using a linear mixed statistical model. There was no difference found in recovery of the toe-spread function between any EMF treatments compared to sham.     

Time-Course Effect of Electrical Stimulation on Nerve Regeneration of Diabetic Rats

BackgroundElectrical stimulation (ES) has been shown to promote nerve regeneration in rats with experimental diabetes induced using streptozotocin (STZ). However, the time-course effect of ES on nerve regeneration of diabetic animals has not been reported in previous studies. The present study attempted to examine the effect of different timing of ES after peripheral nerve transection in diabetic rats.Methodology/FindingsFifty Sprague-Dawley rats were used in the study. They were classified into five groups. STZ-induced diabetes was created in groups A to D. Normal animals in group E were used as the non-diabetic controls. The sciatic nerve was transected and repaired using a silicone rubber conduit across a 10-mm gap in all groups. Groups A to C received ES for 15 minutes every other day for 2 weeks. Stimulation was initiated on day 1 following the nerve repair for group A, day 8 for group B, and day 15 for group C. The diabetic control group D and the normal control group E received no ES. At 30 days after surgery in group A, histological evaluations showed a higher success percentage of regeneration across the 10-mm nerve gap, and the electrophysiological results showed significantly larger mean values of evoked muscle action potential area and amplitude of the reinnervated gastrocnemius muscle compared with group D.Conclusions/SignificanceIt is concluded that an immediate onset of ES may improve the functional recovery of large nerve defect in diabetic animals.     

Pretreatment of rats with pulsed electromagnetic fields enhances regeneration of the sciatic nerve

Regeneration of the sciatic nerve was studied in rats pretreated in a pulsed electromagnetic field (PEMF). The rats were exposed between a pair of Helmholtz coils at a pulse repetition rate of 2 pps at a field density of 60 or 300 μT. The PEMF treatment was then discontinued. After an interval of recovery, regeneration of the sciatic nerve was initiated by a crush lesion. Regeneration of sensory fibers was measured by the “pinch test” after an additional 3–6 days. A variety of PEMF pretreatments including 4 h /day for 1–4 days or exposure for 15 min/day during 2 days resulted in an increased regeneration distance, measured 3 days after the crush lesion. This effect could be demonstrated even after a 14-day recovery period. In contrast, pretreatment for 4 h/day for 2 days at 60 μT did not affect the regeneration distance. The results showed that PEMF pretreatment conditioned the rat sciatic nerve in a manner similar to that which occurs after a crush lesion, which indicates that PEMF affects the neuronal cell body. However, the mechanism of this effect remains obscure. © 1993 Wiley-Liss, Inc.     

碱性成纤维细胞生长因子对大鼠晚期周围神经再生作用的实验研究

目的探讨外源性碱性成纤维细胞生长因子(bFGF)对晚期周围神经再生的作用.方法50只SD大鼠随机分治疗组、对照组各25只,切断右侧坐骨神经,12周后予以修复,修复术后每日分别给予bFGF和生理盐水,行神经电生理和组织学检查.结果治疗组和对照组修复处远段神经均有不同程度再生,4周时已可见到再生轴突,且治疗组多见.计量分析治疗组运动神经传导速度、神经肌肉动作电位幅值、髓鞘厚度、再生轴突直径和截面积明显优于对照组.治疗组与对照组相比,差异有显著性.结论bFGF能促进晚期周围神经再生.     

Transcriptional landscape of alternative splicing during peripheral nerve injury

Alternative splicing (AS) regulates a variety of biological activities in numerous tissues and organs, including the nervous system. However, the existence and specific roles of AS events during peripheral nerve repair and regeneration remain largely undetermined. In the current study, by mapping splice-crossing sequence reads, we identified AS events and relevant spliced genes in rat sciatic nerve stumps following sciatic nerve crush. AS-related genes at 1, 4, 7, and 14 days post nerve crush were compared with those at 0 day to discover alternatively spliced genes induced by sciatic nerve crush. These injury-induced alternatively spliced genes were then categorized to diseases and biological functions, genetic networks, and canonical signaling pathways. Bioinformatic analysis indicated that these alternatively spliced genes were mainly correlated to immune response, cellular growth, and cellular function maintenance. Our study elucidated AS events following peripheral nerve injury and might help deepen our understanding of the molecular mechanisms underlying peripheral nerve regeneration.     

A Silk Fibroin/Collagen Nerve Scaffold Seeded with a Co-Culture of Schwann Cells and Adipose-Derived Stem Cells for Sciatic Nerve Regeneration

As a promising alternative to autologous nerve grafts, tissue-engineered nerve grafts have been extensively studied as a way to bridge peripheral nerve defects and guide nerve regeneration. The main difference between autogenous nerve grafts and tissue-engineered nerve grafts is the regenerative microenvironment formed by the grafts. If an appropriate regenerative microenvironment is provided, the repair of a peripheral nerve is feasible. In this study, to mimic the body’s natural regenerative microenvironment closely, we co-cultured Schwann cells (SCs) and adipose-derived stem cells (ADSCs) as seed cells and introduced them into a silk fibroin (SF)/collagen scaffold to construct a tissue-engineered nerve conduit (TENC). Twelve weeks after the three different grafts (plain SF/collagen scaffold, TENC, and autograft) were transplanted to bridge 1-cm long sciatic nerve defects in rats, a series of electrophysiological examinations and morphological analyses were performed to evaluate the effect of the tissue-engineered nerve grafts on peripheral nerve regeneration. The regenerative outcomes showed that the effect of treatment with TENCs was similar to that with autologous nerve grafts but superior to that with plain SF/collagen scaffolds. Meanwhile, no experimental animals had inflammation around the grafts. Based on this evidence, our findings suggest that the TENC we developed could improve the regenerative microenvironment and accelerate nerve regeneration compared to plain SF/collagen and may serve as a promising strategy for peripheral nerve repair.     

不同激光照射方法对周围神经再生的影响

为研究不同半导体激光照射方法对周围神经损伤的影响,将96只家兔随机分为3周,6周,9周,12周4个观察期组,每个观察期组又随机分为不同照射方法的治疗组和对照组。建立动物模型后,各照射组在术后1d开始照射治疗,激光功率为10mw,每次照射10rain,每天一次,连续照射10d。照射治疗A组对准损伤神经吻合部位进行照射,照射治疗B组照射家兔L5、L6脊髓节段,照射治疗c组在对准吻合处进行照射同时还要照射L5、L6脊髓节段,对照组激光输出功率为零。实验结果表明低能量半导体激光照射能促进轴突再生,改善再生神经功能,以同时照射损伤周围神经部位和相应脊髓节段效果最为显著。     

周围神经再生早期过程中内源性和外源性巨噬细胞数量变化的实验研究

目的：周围神经再生过程中巨噬细胞发挥了重要的作用,然而目前对于神经内内源性和外源性巨噬细胞的具体作用了解的却很少,因此本实验研究了小鼠坐骨神经损伤后早期再生过程中内源性和外源性巨噬细胞数量比例变化的情况,探索周围神经再生的规律。方法：移植CAG-EGFP转基因小鼠的全骨髓有核细胞到骨髓灭活野生型C5781／6小鼠体内建立嵌合体小鼠模型。待移植成功3个月后夹伤小鼠一侧坐骨神经,并在损伤后第2、7、14和28天取材、切片,使用巨噬细胞特异性抗体cD68进行免疫荧光染色,分析损伤神经段中内源性巨噬细胞（CD68＋／EGFP-）、外源性巨噬细胞（CD68＋／EGFP＋）的数量及其比例变化情况。结果：①夹伤骨髓移植模型小鼠坐骨神经后,参与坐骨神经损伤修复的巨噬细胞可分为两类,即内源性巨噬细胞（CD68＋／EGFP-）和外源性巨噬细胞（CD68＋／EGFP＋）;②夹伤坐骨神经后,浸润的总巨噬细胞数量从第2天开始逐渐增加,到第14天达到高峰,约为正常情况下的60倍,随后逐渐减少;③起初外、内源性巨噬细胞间的比例是1：1,差值最大出现在损伤后第14天为4：l。结论：小鼠坐骨神经夹伤后,内外源性巨噬细胞共同参与了受损神经组织远心段的修复和再生过程,损伤初期发挥作用的主要是内源性巨噬细胞,随后大量浸润的外源性巨噬细胞占主导作用。本实验首次连续观察并定量分析了神经损伤后早期内源性和外源性巨噬细胞的数量改变,证实了瓦勒氏变性过程中内源性和外源性巨噬细胞在不同阶段对巨噬细胞总量的贡献作用。     

The peripheral nerve allograft: an assessment of regeneration across nerve allografts in rats immunosuppressed with cyclosporin A

Lewis rats (RT1(1] were the recipients of 3-cm nerve grafts from syngeneic Lewis donors or allogeneic ACI (RT1a) donors. Microneurosurgical repair of the nerve graft to the transected sciatic nerve of the recipient animal was performed with 10-0 epineurial sutures. Recipients were randomly allocated to cyclosporin A (CsA) immunosuppressed or untreated groups. Cyclosporin A was administered in the minimal effective dosage to prevent nerve allograft rejection across this major histocompatibility disparity (5 mg/kg per day). Nerve regeneration across the nerve grafts was assessed by sciatic function index (SFI) and toe spread index (TSI) determinations serially and by electrophysiologic, histologic, and morphologic assessments 14 weeks after engraftment. Sciatic nerve regeneration across allogeneic nerve grafts in cyclosporin A immunosuppressed recipients was significantly superior compared to the untreated controls (p less than 0.008) and not significantly different from that across the syngeneic control animals.     

The process of myelopoiesis in guinea pigs under conditions of a static magnetic field

Myelopoiesis and distribution of white blood cells in peripheral blood in 210 guinea pigs related to the duration and induction of an applied magnetic field were studied. Exposure to a static magnetic field of induction 0.05 T and 0.3 T each day for 7 weeks at 1 h per day led to a decrease of basophilic and polychromatophilic erythroblasts, an increase in the percentage of cells of the granulopoietic (neutrophilic myelocytes, eosinophilic metamyelocytes, band neutrophils, band basophils, segmented eosinophils) and lymphopoietic system, a slight increase in plasma cells and decrease in the percentage of megakaryocytes in bone-marrow. In the peripheral blood the percentage of lymphocytes was increased. The observed changes were independent on the duration of magnetic field action within the magnetic induction value.     

Modulation of peripheral nerve regeneration: a tissue-engineering approach. The role of amnion tube nerve conduit across a 1-centimeter nerve gap

A new type of a biodegradable nerve graft conduit material, the amnion tube, has been developed in our laboratory. To test the tube in the peripheral nerve regeneration process, it was initially applied across a 1-cm sciatic nerve gap in rats and was compared with other nerve conduit materials. We used male Sprague-Dawley rats as our animal model. The experiment included 66 rats that were randomly assigned into five groups: autograft (n = 17), amnion tube (n = 19), silicone tube (n = 20), no repair (n = 7), and sham group (n = 3). The process of peripheral nerve regeneration was evaluated at 2, 4, 10, and 17 weeks following injury and repair by using morphologic and functional assessments of the outcome of nerve regeneration in each animal. Nerve regeneration across the amnion tube nerve conduit was comparable with that seen in autograft and superior to that of the silicone group. A uniform nerve tissue was seen filling and crossing the amnion conduit, and the regenerated nerve from the proximal stump reached the distal end and was undifferentiated from the normal nerve tissues. At 4 months, the amnion tube biodegraded and no longer could be identified and differentiated from the nerve tissues. The amnion tube animal group showed a number of axons very close to that in the nerve autograft group (37,157 versus 33,054). Functional recovery at a 2- to 4-week interval was significantly statistically higher only in the amnion tube animal group (p = 0.01). However, the improvement disappeared between 10 and 17 weeks. In conclusion, the amnion tube is a potential ideal nerve conduit material secondary to its unique characteristics: it contains important neurotropic factors, is biodegradable, provokes a very weak immune response, is semiflexible, is readily available, and is easily manufactured into different sizes and diameters.     

Diabetes Alters Aromatase Enzyme Levels in Sciatic Nerve and Hippocampus Tissues of Rats

Diabetes mellitus (DM) is associated with increased risk of impaired cognitive function. Diabetic neuropathy is one of the most common and important complications of DM. Estrogens prevent neuronal loss in experimental models of neurodegeneration and accelerate nerve regeneration. Aromatase catalyzes the conversion of androgens to estrogens and expressed in a variety of tissues including neurons. Although insulin is known to regulate the activity of aromatase there is no study about the effects of diabetes on this enzyme. Present study was designed to investigate the effects of experimental diabetes on aromatase expression in nervous system. Gender-based differences were also investigated. Rats were injected with streptozotocin to induce diabetes. At the end of 4 and 12 weeks sciatic nerve and hippocampus homogenates were prepared and evaluated for aromatase proteins. Aromatase expressions in sciatic nerves of both genders were decreased in 4 weeks of diabetes, but in 12 weeks the enzyme levels were increased in females and reached to control levels in male animals. Aromatase levels were not altered in hippocampus at 4 weeks but increased at 12 weeks in female diabetic rats. No significant differences were observed at enzyme levels of hippocampus in male diabetic rats. Insulin therapy prevented all diabetes-induced changes. In conclusion, these results indicated for the first time that, DM altered the expression of aromatase both in central and peripheral nervous systems. Peripheral nervous system is more vulnerable to damage than central nervous system in diabetes. These effects of diabetes differ with gender and compensatory neuroprotective mechanisms are more efficient in female rats.