Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / Oxaliplatina (OXL) à um agente platÃnico de 3 geraÃÃo com potente atividade citotÃxica em diversos cÃnceres. Tem como toxicidade limitante uma neuropatia sensitiva perifÃrica (NSP) de inÃcio agudo, tornando-se crÃnica com doses cumulativas. Amifostina (AMF) à um agente antioxidante de largo espectro, que vem sendo atualmente estudado na citoproteÃÃo dos efeitos adversos da radioterapia e quimioterapia do cÃncer. Esta pesquisa objetivou avaliar o efeito da AMF sobre a hiperalgesia mecÃnica plantar e alodinia tÃrmica, assim como sobre as alteraÃÃes histopatolÃgicas e imunoexpressÃo de marcadores, tais como a proteÃna c-Fos, caspase 3, IL-1, nitrotirosina, NOSi, NOSn e NMDA, observadas na NSP experimental induzida por OXL. O estudo foi aprovado pelo Comità de Ãtica em Pesquisa Animal da Universidade Federal do CearÃ, com o protocolo 27/08. Camundongos Swiss machos (25-35g) foram tratados com OXL (1mg/kg, i.v.) e prÃ-tratados com AMF (1, 5, 25, 50 ou 100mg/kg, s.c.) por 4,5 semanas, paralelamente aos testes nociceptivos. A alodÃnia tÃrmica foi avaliada pelo teste de imersÃo da cauda em Ãgua fria (10ÂC) e a hiperalgesia mecÃnica plantar pelo teste do Von Frey EletrÃnico. Foi realizada a anÃlise histopatolÃgica e imunohistoquÃmica de amostras obtidas do corno dorsal da medula espinhal lombar dos animais em 24h, 7, 14, 21 e 28 dias. Demonstrou-se que a OXL diminuiu significativamente o limiar nociceptivo mecÃnico e tÃrmico, a partir do 21 dia (p<0,001) e 14 dia (p<0,01), respectivamente, quando comparados ao grupo controle. O tratamento com AMF inibiu esses efeitos em todas as doses testadas (p<0,001), sendo a dose de 25mg/kg aquela com efeito mais significativo. No teste do Rota-Rod nÃo foi observada variaÃÃo significativa entre os grupos, indicando ausÃncia de comprometimento motor. Na anÃlise histopatolÃgica foram observados edema do tecido nervoso e atrofia dos neurÃnios nos animais tratados com OXL, o que nÃo ocorreu nos animais prÃ-tratados com AMF. Observou-se a imunoexpressÃo importante de c-Fos, caspase 3, NOSn, NOSi e nitrotirosina nos animais tratados apenas com OXL, e uma imunoexpressÃo reduzida do receptor NMDA, quando comparado com o grupo controle. AMF reduziu a expressÃo de c-Fos e de nitrotrosina, mas nÃo da caspase 3, NOSn e NOSi, e aumentou a expressÃo do receptor NMDA. NÃo houve imunoexpressÃo de IL-1 nos grupos testados. Embora preliminares, os dados sugerem que a AMF promoveu uma importante proteÃÃo nas alteraÃÃes sensitivas da NSP induzida por OXL, desde que inibiu a hiperalgesia e a alodinia, alÃm da imunoexpressÃo de c-Fos. Adicionalmente AMF promoveu importante aÃÃo protetora nas lesÃes teciduais, sendo capaz de exercer aÃÃo antioxidante e antiapoptÃtica, atravÃs da inibiÃÃo da expressÃo de nitrotirosina e do aumento da expressÃo do receptor NMDA, respectivamente. / Oxaliplatin (OXP) is a third-generation platinum agent with potent cytotoxic activity in several cancers. Its limiting toxicity is a sensory peripheral neuropathy (SPN) of acute onset, which becomes chronic after cumulative doses. Amifostine (AMF) is a broad spectrum antioxidant and is currently being studied as a cell-protecting agent against the adverse effects of radiotherapy and chemotherapy in cancer patients. This study was aimed to evaluate the effect of AMF on plantar mechanical hyperalgesia and thermal allodynia, as well as on histopathological alterations and immune expression of markers such as c-Fos protein, caspase 3, IL-1, nitrotyrosine, iNOS, nNOS and NMDA, observed in experimental OXL-induced SPN. The study was approved by the Ethics Committee on Animal Research, Federal University of CearÃ, through protocol 27/08. Male Swiss mice (25-35g) were treated with OXL (1 mg/kg, i.v.) and pre-treated with AMF (1, 5, 25, 50 or 100 mg/kg, s.c.) for 4,5 weeks, in addition to the performance of nociceptive tests. Thermal allodynia was evaluated by tail immersion in cold water (10ÂC), and plantar mechanical hyperalgesia by the Electronic Von Frey test. The histopathological and immunohistochemical analysis of samples taken from the dorsal horn of the lumbar spinal cord of the animals was performed in 24 hours, 7, 14, 21 and 28 days. OXP significantly decreased mechanic and thermal nociceptive threshold since 21th day (p<0,001) and 14th day (p<0,01), respectively, when compared to control group. AMF treatment inhibited these effects in all doses tested (p<0,001), and the dose of 25mg/kg had the most significant effect. Locomotor impairment was not evidenced through Rota-Rod test. Furthermore, we observed edema and neurons atrophy in dorsal horn of OXP group, not showed in AMF group. OXP group had overexpression of c-Fos, caspase 3, nNOS, iNOS, and nitrotyrosine, but a reduced NMDA receptor expression when compared to control group. AMF group had hypoexpression of c-Fos and nitrotyrosine and increased NMDA receptor expression, but not altered caspase 3, nNOS and iNOS expression. There was no immunoexpression of IL-1 in the tested groups. Although preliminary, the data suggest that AMF promoted an important protection in OXL-induced SPN sensory changes, since it inhibited the hyperalgesia and allodynia, as well as the immunoexpression of c-Fos. Additionally AMF promoted significant protective action on tissue lesions, being able to exert antioxidant and antiapoptotic action by inhibiting the expression of nitrotyrosine and increasing expression of NMDA receptors, respectively.

Abstract The arm includes a large number of nerve fibres that transfer information between the central nervous system and the receptors, muscles and glands of the arm. In the nervous system there is continuous traffic. At rest, when only the receptors send information continuously towards the central nervous system, the traffic is not as intensive as during stress, e.g. during movements of the arm, when the central nervous system sends information towards the muscles, as well. From an information and communication engineering perspective the nervous system of the arm is an information channel, the other end of which is in the central nervous system and the other end at the periphery of the arm. One principal question about such a communication system is what the maximum information transmission capacity of the channel is, e.g. how the information channel is dimensioned. The arm is a highly complex system with over sixty muscles moving it, and a huge number of sensory receptors in it. Nature has dimensioned the information channel of the arm to satisfy the requirements of the nervous system. In this thesis a specific mathematical model is built in order to evaluate the maximum information transmission capacity of the nervous system of the arm. The model handles the nervous system of the arm as an entity in the light of information theory. The model uses the physiological and functional properties of the nervous system of the arm as the input and gives the estimate of the maximum information transmission capacity as the output. The modelling yielded the result that the maximum information transmission capacity of the arm is about 10 Mbit/s. Hence, if a complete neural prosthesis of the arm were built, a single USB bus (12 Mbit/s) would suffice as a communication channel for each arm. The mathematical model developed can also be applied to other parts of the peripheral nervous system. The aim of future research is to apply the developed model comprehensively to the human peripheral nervous system and to estimate the maximum information transmission capacity of the whole human peripheral nervous system.

The mouse nervous system undergoes a vast remodelling of synaptic connections postnatally, resulting in a reduced number of innervating axons to target cells within the first few weeks of life. This extensive loss of connections is known as synapse elimination and it plays a critical role in sculpting and refining neural connectivity throughout the nervous system, resulting in a finely tuned and well-synchronised network of innervation. This process has been well characterised at the mouse neuromuscular junction (NMJ), where synapse elimination takes place postnatally in all skeletal muscles. It has been well studied for the reasons that it is easily accessible for live imaging and post-mortem experimental analysis. Studies utilising this synapse to uncover regulators of synapse elimination have mainly focused on the importance of glial cell lysosomal activity, nerve conduction and target-derived growth factor supply. It is clear that non-axonal cell types play key roles in the success of developmental axon retraction at the NMJ, however the role of glial cells in the regulation of this process has not been fully explored, as lysosomal activity is thought of as a consequence of axon pruning rather than a molecular driver. Previous studies have shown that signals emanating from myelinating glial cells can modulate neurofilament composition and transport within the underlying axons. We know that these changes in neurofilament composition and transport are underway during developmental synapse elimination at the NMJ, so it seems logical to predict that myelinating glial cells may play a role in the regulation of axonal pruning. Myelinating glial cells are found along the entire length of lower motor neurons and form physical interactions with the underlying axons at regions known as paranodes. At the paranode, Neurofascin155 (Nfasc155: expressed by the myelinating glial cell) interacts with a Caspr/contactin complex (expressed by the axon). This site has been proposed as a likely site for axon-glial signalling due to the close apposition of the cell membranes. The main focus of this PhD project was to study the potential role of myelinating glial cells in the success of synapse elimination at the NMJ, using a mouse model of paranodal disruption (Nfasc155-/-). Chapters 3 and 4 show the results of this work. This work has revealed a novel role for glia in the modulation of synapse elimination at the mouse neuromuscular junction, mediated by Nfasc155 in the myelinating Schwann cell. Synapse elimination was profoundly delayed in Nfasc155-/- mice and was found to be associated with a non-canonical role for Nfasc155, as synapse elimination occurred normally in mice lacking the axonal paranodal protein Caspr. Loss of Nfasc155 was sufficient to disrupt axonal proteins contributing to cytoskeletal organisation and trafficking pathways in peripheral nerve of Nfasc155-/- mice and lower levels of neurofilament light (NF-L) protein in maturing motor axon terminals. Synapse elimination was delayed in mice lacking NF-L, suggesting that Nfasc155 influences neuronal remodelling, at least in part, by modifying cytoskeletal dynamics in motor neurons. This work provides the first clear evidence for myelinating Schwann cells acting as drivers of synapse elimination, with Nfasc155 playing a critical role in glial cell-mediated postnatal sculpting of neuronal connectivity in the peripheral nervous system. A small section of the results within this thesis are devoted to the study of axon-glial interactions in a mouse model of childhood motor neuron disease, otherwise known as spinal muscular atrophy (SMA). In SMA, there are reduced levels of the ubiquitously expressed survival motor neuron (SMN) protein. The NMJ is a particularly vulnerable target in SMA, manifesting as a breakdown of neuromuscular connectivity and progressive motor impairment. Recent studies have begun to shed light on the role of non-neuronal cell types in the onset and progression of the disease, presenting SMA as a multi-system disease rather than a purely neuronal disorder. Recent evidence has highlighted that myelinating glial cells are significantly affected in a mouse model of SMA, manifesting as an impaired ability to produce key myelin proteins, resulting in deficient myelination. The final results chapter of this thesis (Chapter 5) is focussed on further exploring the effects that loss of SMN has in Schwann cells including their interactions with underlying axons. This work reveals a disruption to axon-glial interaction, shown by a delay in the development of paranodes, supporting the idea that non-neuronal cell types are also affected in SMA. The results within this thesis reveal a novel role for a glial cell protein, Nfasc155, in the modulation of synapse elimination at the NMJ. Mechanistic insight in to Nfasc155’s role in this process is also uncovered and likely involves axonal cytoskeletal transport systems and the filamentous protein NF-L, which have not previously been implicated in the process of synapse elimination. This work highlights an important role for axon-glial interactions during normal postnatal development of the mouse NMJ. This work also highlights a role for axon-glial interactions in disease states of the NMJ. Using a mouse model of SMA, axon-glial interaction was assessed with the finding of a delay in paranodal maturation due to loss of SMN.

Primary cilia are ubiquitous sensory organelles found on most cell types including cells of the dorsal root ganglia (DRG). The DRG are groups of peripheral neurons that relay sensory information from the periphery to the CNS. Other cell types in the DRG include a type of glial cell, the satellite glial cells (SGCs). The SGCs surround the DRG neurons and, with the neurons, form functional sensory units. Currently are no reports describing the numbers of DRG cells that have cilia. We found that 26% of the SGCs had primary cilia. The incidence of cilia on neurons varied with neuron size, a property that roughly correlates with physiological characteristics. We found that 29% of the small, 16% of the medium and 5% of the large neurons had primary cilia. Primary cilia have been shown to have a role in cell proliferation in a variety of cell types. In some of the cells the cilia mediate the proliferative effects of Sonic hedgehog (Shh). In the CNS, Shh signaling through primary cilia affects proliferation during development as well as following injury, but no studies have looked at this function in the PNS. The SGCs and neurons of the DRG undergo complex changes following peripheral nerve injury such as axotomy. One marked change seen after axotomy is SGC proliferation and at later stages, neuronal death. We found that following axotomy there is a significant increase in the percentage of SGCs with primary cilia. We also found a significant increase in the percentage of medium-sized neurons with primary cilia. In other experiments we tested the idea that Shh plays a role in SGC proliferation. When Shh signaling was blocked following axotomy we found decreased proliferation of SGCs. This is the first report of a change in the percentage of cells with cilia following injury in the PNS, and the first report of a role for Shh in SGC proliferation following axotomy.

A dissertation submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of MSc (Med) Johannesburg, 2011 / Peripheral sensory neuropathy is a common neurological complication of antiretroviral therapy, typically occurring within 6-months of starting Highly Active Antiretroviral Therapy (HAART) which includes stavudine. Therefore, the primary aim of the study was to determine the 6-month incidence of ATN in patients free of neuropathy and beginning stavudine-based HAART for the first time. Also, we examined whether initiating stavudine-based HAART altered the symptoms of patients who had a pre-existing, virus-mediated distal symmetrical polyneuropathy (HIV-DSP). Seventy-five HIV-positive patients were screened for neuropathy, at the Chris-Hani Baragwanath Hospital, using the AIDS Clinical Trials Group neuropathy screening tool. The bilateral presence of atleast one sign (decreased vibration sense in the great toe or absent ankle reflex) and one symptom (pain, paraesthesia or numbness) in the feet was indicative of neuropathy. On recruitment, 52 patients presented without neuropathy and 13 patients presented with HIV-DSP. After 3- months of follow-up (n=46), 23% (10/46) of patients had developed peripheral neuropathy, and by 6-months (n=44), 41% (18/44) of patients had developed neuropathy. Greater disease severity was the only risk factor significantly associated with the development of neuropathy. Eleven (61%) of the 18 patients that developed neuropathy, developed painful symptomatic neuropathy, and only 6 (55%) of these patients were receiving treatment for symptom relief. In patients with HIV-DSP, numbness was the most common symptom reported at baseline and was the only symptom to reduce in frequency across the 6-months. In conclusion, we found that the development of neuropathy is common in the first 6-months of patients initiating stavudine-based HAART.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Myelin facilitates the timely, efficient conduction of action potentials along axons. Made by Schwann cells (SCs) in the PNS, myelin is unique in that it is composed of a high percentage of lipids, particularly galactolipids. Sulfatide, one such galactolipid, is made by cerebroside sulfotransferase (CST) and has been shown to play a role in organizing paranodal domains in myelinated axons. However less is known regarding the involvement of sulfatide in the establishment and maintenance of the node, of particular interest as it is responsible for the potentiation of action potentials along the axon. Using immunohistochemical and, to a lesser extent, electron microscopic techniques, we confirm that sulfatide is essential for organization of the paranode. Our data further shows that neuronal nodal clustering and maintenance is paranode-independent, thus not reliant on sulfatide, demonstrating that 1) distinct mechanisms exist for nodal and paranodal organization 2) distinct mechanisms for nodal stability exist in the PNS versus the CNS. Interestingly, maintenance of the SC nodal protein, gliomedin, is sulfatide-dependent, indicating that sulfatide is differentially important for nodal organization depending on the cell of origin. Finally, we observe that despite compromised molecular organization of the nodal and paranodal domains in the absence of sulfatide, the gross structure is preserved, therefore a disconnect exists between molecular and structural organization.

HIV-associated peripheral neuropathy (PN), and related functional limitations that affect the quality of life (QoL), may now be one of the most formidable challenges in the health care of people living with HIV (PLHIV). The most common PN is distal sensory polyneuropathy (DSP). It is likely that there is a high prevalence of PN among PLHIV in Rwanda. The available data on the prevalence of PN are poor and there are none on how PN is associated with functional abilities and the QoL of PLHIV, which can guide management. In addition, current management of PN is mostly related to symptomatic management and is mainly pharmacological which may not rehabilitate the neuromuscular function that has been affected by PN. This thesis planned to re-validate and adapt the lower extremity functional scale (LEFS) and the brief peripheral neuropathy screen (BPNS), establish the prevalence of PN, and determine the effects of physiotherapeutic exercises on PN, lower extremity functional limitations and QoL, among Rwandan PLHIV receiving antiretroviral therapy (ART). Methods Study 1 translated LEFS from English to Kinyarwanda, modified it accordingly, and tested its reliability among 50 adult PLHIV on ART. The study also piloted

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