Ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) each promote the survival and differentiation of developing motor neurons, but do so through distinct cellular signaling pathways. Administration of either factor alone has been shown to slow, but not to arrest, progression of motor neuron dysfunction in wobbler mice, an animal model of motor neuron disease. Because CNTF and BDNF are known to synergize in vitro and in ovo, the efficacy of CNTF and BDNF cotreatment was tested in the same animal mode. Subcutaneous injection of the two factors on alternate days was found to arrest disease progression in wobbler mice for 1 month, as measured by several behavioral, physiological, and histological criteria.

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Depression and anxiety are common in Parkinson's disease (PD) and have important consequences on quality of life. These have long been recognized as frequent accompanying syndromes of PD, and several reports suggest that these are the causative process or risk factors that are present many years before the appearance of motor symptoms. The neurochemical changes in PD involving dopamine, norepinephrine, and serotonin might be related to the pathophysiology of depression and anxiety, but this is still not clear. Several studies showed that anxiety in PD patients occurs earlier than depression, during premotor phase, suggesting that there may be a link between the mechanisms that cause anxiety and PD. Whereas a recent study reported that PD patients with depression and anxiety were associated with different demographic and clinical features.

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Background: Clinicoradiological variability of vertebrobasilar dolichoectasia (VBD) is known. Little is known about cardiovascular disease (CVD) risk and neuroradiological profiles of asymptomatic VBD. Methods: A total of 7,345 adults (5,534 men and 1,811 women) underwent physical checkup (PC) and brain magnetic resonance (MR) studies between 2004 and 2007. Asymptomatic VBD was diagnosed by neurological examination and MR angiography. Neuroradiological features were analyzed in VBD subjects. CVD risk factors were compared between VBD subjects and 5,000 controls matched by sex and age. Results: Ninety-six subjects (85 men and 11 women) had asymptomatic VBD. The detection rate was 1.3% and the male/female ratio 2.5. The mean age ± SD was 60.4 ± 10.6 years (60.0 ± 10.2 in men and 64.0 ± 13.1 in women). As compared to controls, the frequency of hypertension, obesity, smoking, dyslipidemia, diabetes mellitus and a family history of stroke or CVD was increased significantly in VBD subjects. The mean diameter ± SD of the basilar artery (BA) was 4.7 ± 0.2 mm. Only 4 subjects (4%) had a severe degree of elongation and lateral displacement of the BA. Contact of the vertebral artery with the rostral ventrolateral medulla (AMC) was found in 81 subjects: right AMC in 22 subjects and left AMC in 59 subjects. Frequency of hypertension was significantly higher in the left-AMC subjects (57%) than in subjects with right AMC (9%) and no AMC (5%). Other neuroradiological findings revealed small infarcts in 42 subjects, brainstem compression in 4, hydrocephalus in 4 and brain saccular aneurysm in 3. Conclusions: Asymptomatic VBD was detected in 1.3% of the Japanese PC group. Our data indicated male predominance, multiple CVD risk factors, neurovascular hypertension and small infarcts in asymptomatic VBD.

Ciliary neurotrophic factor is the first neurotrophic factor to show survival-promoting effects in developing motor neurons in vitro, in ovo, and in vivo. In the present study we tested the effects of recombinant rat or human ciliary neurotrophic factor in the wobbler mouse model of motor neuron disease. Mice received 1 mg/kg of the factor or a vehicle solution subcutaneously three times a week for 4 weeks, after the disease was diagnosed between the ages of 3 and 4 weeks. Although treatment with rat ciliary neurotrophic factor (n = 6) resulted in delayed weight gain (p < 0.001), grip strength normalized to body weight in the factor-treated mice was significantly greater (p < 0.02) and declined at a slower rate (p < 0.05) compared to that in vehicle-treated animals. Human ciliary neurotrophic factor (n = 27) produced no change in body weight and reduced paw position and walking pattern abnormalities (p < 0.001 and p < 0.02, respectively). After 4 weeks of treatment, the mean grip strength of human ciliary neurotrophic factor-treated animals was twice as great (p < 0.001) and declined at a much slower rate (p < 0.005) than that of control mice. The time required to run 2.5 ft was less (p < 0.005) and muscle twitch tension was greater (p < 0.002) in ciliary neurotrophic factor-treated animals. Thus, ciliary neurotrophic factor retarded the disease progression and improved muscle strength in this motor neuron disease model.

Brain-derived neurotrophic factor (BDNF) has been shown to promote the survival of developing motor neurons in vitro and to rescue motor neurons from axotomy-induced cell death in vivo. In this study, we examined the effects of exogenous BDNF on the progression of wobbler mouse motor neuron disease (MND). After clinical diagnosis at age 3 to 4 weeks, 20 affected mice received subcutaneous injections of recombinant human BDNF (5 mg/kg, n = 10) or vehicle (n = 10), three times a week for 4 weeks. In a separate experiment done to conduct a histometric analysis of the C-5 and C-6 ventral roots and to determine the number of myelinated nerve fibers, 7 wobbler mice received identical BDNF treatment. In the 10 BDNF-treated wobbler mice, grip strength declined at a slower rate (p < 0.03) and was twice as great as that of vehicle-treated animals at the end of treatment (p < 0.01). In vivo biceps (p < 0.01) and in vitro muscle twitch tensions (p < 0.02) were also greater than those of vehicle-treated mice. The biceps muscle weight was 20% greater (p < 0.05) and the mean muscle fiber diameter was significantly larger in BDNF-treated mice (p < 0.001) because the number of small (denervated) muscle fibers was markedly reduced. The number of myelinated motor axons at the cervical ventral roots studied in the additional 7 affected mice was 25% greater with BDNF treatment (p < 0.0001). This study establishes that exogenous BDNF administration can retard motor dysfunction in a natural MND and diminish denervation muscle atrophy and motor axon loss.

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