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<p>Neurotrophic factors and their receptors are crucial for the formation of neuronal connections and for the neuronal survival during embryonic development of the nervous system. This has particularly been shown by studies of the PNS. The work of this thesis has aimed at clarifying where and when in the developing retina and its tectal target (as parts of the CNS), certain neurotrophic factors come into play. In a functional perspective, the focus has been on the possible involvement of these factors in the regulation of cell death / survival. Therefore, naturally occuring cell death in the developing avian retina was first studied. From the results, it is concluded that there is an early and a late phase of cell death in the developing retina. The cells dying during the early phase are proliferating retinal precursor cells, and the cells dying later are in the process of terminal differentiation. The timing and distribution of the dying cells suggest that the cell death is regulated. During retinal development two retinal cell types, amacrine cells and horizontal cells, express TrkA, a receptor for the neurotrophin nerve growth factor (NGF). These amacrine cells are shown to undergo cell death during the late cell death phase, but can be rescued by exogenous NGF. The horizontal cells in turn, are supported by NGF in an autocrine manner, and therefore survive. Two other neurotrophic factors brain-derived neurotrophic factor (BDNF) and glial cell-line derived neurotrophic factor (GDNF) are both expressed in the retina and in the target for retinal ganglion cells, the optic tectum. By the results, it is concluded that neuronal activity can regulate the expression of BDNF in the retina and optic tectum. Furthermore, GDNF can stimulate neurite outgrowth from retinal explants of a certain age. Taken together, the main result of this thesis is that neurotrophic factors indeed can work as autocrine survival factors in the developing CNS. </p>

<p>Members of the transforming growth factor-β (TGF-β) superfamily exhibit a range of effects on a host of different cell types. They signal through heteromeric complexes of serine/threonine kinase receptors of type I and type II. Gene targeted mutations of both factors and receptors have revealed that many of them are involved in early embryonic development. This thesis examines the receptors for this superfamily in the nervous system, especially bone morphogenetic protein receptor type II (BMPR-II). It was cloned from chicken nervous tissue, and its and other receptors’ expression in peripheral ganglia, spinal cord and brain of chicken, rat and mouse were examined. BMPR-II, ActR-II and ActR-IA were abundantly expressed throughout development in the nervous system, however with temporal regulation. One ligand of BMPR-II, BMP-7, was found to act synergistically with NT-3 and GDNF on subsets of peripheral neurons to promote survival and neurite outgrowth. A knock-in mouse was generated, encoding a truncated form of BMPR-II coupled to the endogenous tyrosine hydroxylase (TH) gene with an internal ribosome entry site (IRES). For ES-cell selection, a neomycin resistance gene was incorporated into the construct. Homozygous mice carrying the knock-in allele exhibited a small, hypokinetic phenotype. Levels of dopamine, noradrenaline and serotonin were measured, and the catecholamines were found to be lowered, dopamine as much as 97% in the caudate nucleus. The low catecholamine levels may not be an effect of the truncated BMPR-II, but rather a consequence of the knock-in construct reducing TH transcriptional rate. The TH hypomorphic mouse strain generated could find use as a model for catecholamine impaired systems, as seen in Parkinson’s disease.</p>

<p>Stress incontinence and overactive bladder are disorders with a common symptom, urinary incontinence, which is a serious medical and social handicap. Several neurotransmitters regulate the function of the lower urinary tract, including noradrenaline, acetylcholine, and serotonin.</p><p>The present study is part of the search for pharmacological incontinence drugs. The aims of this thesis were to improve the existing pharmacological treatments of urinary incontinence and to look for alternative treatments: i) an α₁-adrenergic agonist that preferentially affects urethral over blood pressure was tested <i>in vivo</i>; ii) a modified cystometry model was developed for screening of muscarinic antagonists, by construction of a complete dose-response curve in each individual animal; iii) a new muscarinic antagonist, PNU-171990, was pharmacologically characterized <i>in vitro</i> and <i>in vivo</i>; iv) functional differences of the isomers of the muscarinic agonist BM-5 were characterized in the urinary bladder and ileum, <i>in vitro</i> and <i>in vivo</i>; v) the role of serotonin 5-HT_2A, 5-HT₃ and 5-HT₄ receptors were characterized on urinary bladder contractions <i>in vivo</i>.</p><p>In the search for urethra selective compounds, the α₁-adrenoceptors agonists phenylephrine and phenylpropanolamine selectively enhanced blood pressure as compared to the urethral pressure in rabbit. This is in contrast to the effect of oxymetazoline and NS-49. Muscarinic antagonists produced a dose-dependent inhibition of the volume-induced micturition pressure in the rat. PNU-171990, a non-selective muscarinic antagonist, revealed selectivity for urinary bladder pressure over salivation (P<0.05). (R)-BM-5 induced bladder contraction and saliva secretion in cats. The selective serotonin 5-HT_2A and 5-HT₃ receptor antagonists, ketanserin and tropisetron, both inhibited the effect of chemically induced bladder contraction in the anaesthetized cat.</p><p>In conclusion, an urethral-selective α_1A-adrenoceptor agonist may be a good treatment of stress incontinence. A bladder-selective competitive muscarinic antagonist is considered a good pharmacotherapy for overactive bladder. In addition, the 5-HT_2A and 5-HT₃receptor antagonist may improve lower urinary tract symptoms.</p>

Neurotrophic factors and their receptors are crucial for the formation of neuronal connections and for the neuronal survival during embryonic development of the nervous system. This has particularly been shown by studies of the PNS. The work of this thesis has aimed at clarifying where and when in the developing retina and its tectal target (as parts of the CNS), certain neurotrophic factors come into play. In a functional perspective, the focus has been on the possible involvement of these factors in the regulation of cell death / survival. Therefore, naturally occuring cell death in the developing avian retina was first studied. From the results, it is concluded that there is an early and a late phase of cell death in the developing retina. The cells dying during the early phase are proliferating retinal precursor cells, and the cells dying later are in the process of terminal differentiation. The timing and distribution of the dying cells suggest that the cell death is regulated. During retinal development two retinal cell types, amacrine cells and horizontal cells, express TrkA, a receptor for the neurotrophin nerve growth factor (NGF). These amacrine cells are shown to undergo cell death during the late cell death phase, but can be rescued by exogenous NGF. The horizontal cells in turn, are supported by NGF in an autocrine manner, and therefore survive. Two other neurotrophic factors brain-derived neurotrophic factor (BDNF) and glial cell-line derived neurotrophic factor (GDNF) are both expressed in the retina and in the target for retinal ganglion cells, the optic tectum. By the results, it is concluded that neuronal activity can regulate the expression of BDNF in the retina and optic tectum. Furthermore, GDNF can stimulate neurite outgrowth from retinal explants of a certain age. Taken together, the main result of this thesis is that neurotrophic factors indeed can work as autocrine survival factors in the developing CNS.

Members of the transforming growth factor-β (TGF-β) superfamily exhibit a range of effects on a host of different cell types. They signal through heteromeric complexes of serine/threonine kinase receptors of type I and type II. Gene targeted mutations of both factors and receptors have revealed that many of them are involved in early embryonic development. This thesis examines the receptors for this superfamily in the nervous system, especially bone morphogenetic protein receptor type II (BMPR-II). It was cloned from chicken nervous tissue, and its and other receptors’ expression in peripheral ganglia, spinal cord and brain of chicken, rat and mouse were examined. BMPR-II, ActR-II and ActR-IA were abundantly expressed throughout development in the nervous system, however with temporal regulation. One ligand of BMPR-II, BMP-7, was found to act synergistically with NT-3 and GDNF on subsets of peripheral neurons to promote survival and neurite outgrowth. A knock-in mouse was generated, encoding a truncated form of BMPR-II coupled to the endogenous tyrosine hydroxylase (TH) gene with an internal ribosome entry site (IRES). For ES-cell selection, a neomycin resistance gene was incorporated into the construct. Homozygous mice carrying the knock-in allele exhibited a small, hypokinetic phenotype. Levels of dopamine, noradrenaline and serotonin were measured, and the catecholamines were found to be lowered, dopamine as much as 97% in the caudate nucleus. The low catecholamine levels may not be an effect of the truncated BMPR-II, but rather a consequence of the knock-in construct reducing TH transcriptional rate. The TH hypomorphic mouse strain generated could find use as a model for catecholamine impaired systems, as seen in Parkinson’s disease.

Stress incontinence and overactive bladder are disorders with a common symptom, urinary incontinence, which is a serious medical and social handicap. Several neurotransmitters regulate the function of the lower urinary tract, including noradrenaline, acetylcholine, and serotonin. The present study is part of the search for pharmacological incontinence drugs. The aims of this thesis were to improve the existing pharmacological treatments of urinary incontinence and to look for alternative treatments: i) an α1-adrenergic agonist that preferentially affects urethral over blood pressure was tested in vivo; ii) a modified cystometry model was developed for screening of muscarinic antagonists, by construction of a complete dose-response curve in each individual animal; iii) a new muscarinic antagonist, PNU-171990, was pharmacologically characterized in vitro and in vivo; iv) functional differences of the isomers of the muscarinic agonist BM-5 were characterized in the urinary bladder and ileum, in vitro and in vivo; v) the role of serotonin 5-HT2A, 5-HT3 and 5-HT4 receptors were characterized on urinary bladder contractions in vivo. In the search for urethra selective compounds, the α1-adrenoceptors agonists phenylephrine and phenylpropanolamine selectively enhanced blood pressure as compared to the urethral pressure in rabbit. This is in contrast to the effect of oxymetazoline and NS-49. Muscarinic antagonists produced a dose-dependent inhibition of the volume-induced micturition pressure in the rat. PNU-171990, a non-selective muscarinic antagonist, revealed selectivity for urinary bladder pressure over salivation (P&lt;0.05). (R)-BM-5 induced bladder contraction and saliva secretion in cats. The selective serotonin 5-HT2A and 5-HT3 receptor antagonists, ketanserin and tropisetron, both inhibited the effect of chemically induced bladder contraction in the anaesthetized cat. In conclusion, an urethral-selective α1A-adrenoceptor agonist may be a good treatment of stress incontinence. A bladder-selective competitive muscarinic antagonist is considered a good pharmacotherapy for overactive bladder. In addition, the 5-HT2A and 5-HT3 receptor antagonist may improve lower urinary tract symptoms.

Objectives: The purpose of this medical thesis was to describe the clinical and neurophysiological features and to evaluate the health related quality of life (HR-QoL) in patients with cryptogenic polyneuropathy. We also wanted to investigate different occupational, and leisure time exposures as determinants for cryptogenic polyneuropathy, and to analyze whether polymorphisms for the null alleles of Glutathione S-Transferase Mu-1 (GSTM1), and Theta-1 (GSTT1), and a low activity genetic variation of epoxide hydrolase (EPHX) affect the risk of developing polyneuropathy. These genes were chosen because their enzymes are important in the metabolism of toxic compounds. Methods: The medical records of all patients aged 40–79 years with the diagnosis of cryptogenic polyneuropathy from 1993 to 2000 were analyzed, and data regarding clinical symptoms, laboratory findings, and neurophysiological findings at diagnosis were collected. 255 cases were found. When the medical records were reevaluated assessment to a protocol 168 patients remained as cryptogenic. Two validated instruments (SF-36 and EQ-5D) for measuring HR-QoL were sent to patients, and a reference group from the general population. Additional clinical information, and data on occupational, and leisure time exposure was obtained from postal questionnaires. Crude odds ratios (COR), and logistic regression odds ratios (LOR) were calculated for exposures with five or more exposed cases and referents taken together. We also tested for genetic polymorphisms of GSTM1 and GSTT1, and epoxide hydrolase exon three, EPHX*3. Results: 68% of the patients were men. The mean age at first symptom was 61 years and at diagnosis 64 years. Distal numbness was the most common symptom, but pain, pedal paresthesias, and impairment of balance were also common. The most common clinical findings were decreased or lost proprioception or sense of vibration (80%), and loss of ankle jerks (78%). Neurography showed mixed sensorimotor polyneuropathy of axonal or mixed axonal and demyelinating type. QOL was significantly affected concerning motor functions, with 42% of the patients reporting problems to walk, 3% having problems with daily activities, and 85% were suffering from pain. Mental health was preserved. Mobility was declining with increasing age, but was not affected by disease duration. Increased risks were found in men for occupational exposure to sulphur dioxide, xylene, methyl ethyl ketone, and herbicides and in women for occupational exposure to lead, nitrous oxide, and insecticides. Interaction between occupational and leisure time exposure were seen for several exposures. No significant correlation was found between GSTM1, GSTT1, and EPHX1 polymorphisms in patients with cryptogenic polyneuropathy compared with controls. A tendency, however, was seen for the GSTT1 null phenotype, which was enhanced among smokers compared to controls (OR 3.7). Conclusions: Cryptogenic polyneuropathy is a slowly progressive sensorimotor nerve lesion of mainly axonal type. Patients with cryptogenic polyneuropathy have a lower QOL compared to the general population, although mental health scores did not differ between the groups. Our results show that known determinants could be confirmed, but also some new appeared i.e. sulphur dioxide, hydrogen sulphide, fungicides, and vibrations in the feet. Moreover our results point to a synergistic effect of various exposures. Our hypothesis is that the GSTT1 null polymorphism may be related to an impaired metabolism of toxic substances and reactive oxygen that could lead to nerve damage in the peripheral nervous system. Our results are indicating that components in cigarette smoke might increase the risk of axonal neuropathy in genetically predisposed patients.

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