ro13-9904 and Neurodegenerative-Diseases

Several neurodegenerative disorders, namely Parkinson's disease dementia, dementia with Lewy bodies, and Alzheimer's disease, share common pathophysiological features, such as (1) cognitive deficits, (2) glutamatergic hyperactivity-related excitotoxicity, and (3) deposition of α-synuclein (α-syn) and β-amyloid (Aβ). Ceftriaxone (CEF) is a well-tested and safe drug that has been used as an antibiotic for several decades. Recent studies have demonstrated the following effects of CEF: (1) increasing glutamate transporter-1 expression and glutamate reuptake and suppressing excitotoxicity, (2) binding well with α-syn and inhibition of α-syn polymerization, (3) modulating expression of genes related to Aβ metabolism, and (4) enhancing neurogenesis and recovery of neuronal density. In addition, our data revealed that CEF ameliorates seizure and abnormal neuronal firing in the brain. These results suggest the potential of CEF in treating neuronal disorders. This paper addresses the effects and pharmacology of CEF.

Topics: Alzheimer Disease; Brain; Ceftriaxone; Humans; Lewy Body Disease; Nervous System Diseases; Neurodegenerative Diseases; Neurogenesis; Neurons; Neuroprotective Agents; Parkinson Disease

Dementia with Lewy bodies (DLB) is characterized by neuronal deficits and

Topics: alpha-Synuclein; Animals; Brain; Ceftriaxone; China; Dementia; Disease Models, Animal; Hippocampus; Lewy Bodies; Lewy Body Disease; Magnetic Resonance Imaging; Male; Neurodegenerative Diseases; Neurons; Rats; Rats, Wistar

Manganese-enhanced magnetic resonance imaging (MEMRI) is a widely used technique for detecting neuronal activity in the brain of a living animal. Ceftriaxone (CEF) has been shown to have neuroprotective effects in neurodegenerative diseases. The present study was aimed at clarifying whether, in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) rat model, the known CEF-induced neuronal protection was accompanied by neurogenesis and decreased loss of neuronal activity. After MPTP lesioning (day 0), the rats were treated with CEF (100mg/kg/day, i.p.) or saline for 15 days. They were then injected with MnCl2 (40mg/kg, i.p.) on day 13 and underwent a brain MRI scan on day 14, then the brain was taken for histological evaluation on day 15. The results showed that MPTP lesioning resulted in decreased neuronal activity and density in the nigrostriatal dopaminergic (DAergic) system and the hippocampal CA1, CA3, and dentate gyrus (DG) areas and reduced neurogenesis in the DG, but in hyperactivity in the subthalamic nucleus (STN). These neuronal changes were prevented by CEF treatment. Positive correlations between MEMRI R1 values and neuronal density in the hippocampus were evidenced. Neuronal densities in the hippocampus and SNc were positively correlated. In addition, the R1 value of the STN showed a positive correlation with its neuronal activity but showed a negative correlation with the density of DAergic neurons in the SNc. Therefore, MEMRI R1 value may serve as a good indicator for PD severity and the effect of treatment. To our knowledge, this is the first study showing that CEF prevents loss of neuronal activity and neurogenesis in the brain of PD rats. CEF may therefore have clinical potential in the treatment of PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Analysis of Variance; Animals; Brain; Brain Mapping; Bromodeoxyuridine; Ceftriaxone; Disease Models, Animal; Electron Transport Complex IV; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; MPTP Poisoning; Neurodegenerative Diseases; Neurogenesis; Neuroprotective Agents; Rats; Rats, Wistar; Statistics as Topic; Tyrosine 3-Monooxygenase

Young-onset dementias pose a major challenge to both clinicians and researchers. Cognitive decline may be accompanied by systemic features, leading to a diagnosis of "dementia plus" syndromes. Whipple disease is a rare systemic illness characterized by arthralgias, chronic diarrhea, weight loss, fever, and abdominal pain. Central nervous system involvement, including severe cognitive deterioration, may precede systemic manifestations, appear during the course of the disease, or even be the only symptom. We report a previously highly functional 48-year-old man whom we first suspected of having early-onset neurodegenerative dementia but then diagnosed with Whipple disease based on a detailed clinical and laboratory evaluation. Initial neuropsychological evaluation revealed marked impairment in the patient's fluid intelligence and severe cognitive deficits in his information processing speed, complex attention, memory, visuomotor and construction dexterities, problem solving, and executive functions. At neuropsychological follow-up 21 months later, his information processing speed had improved only slightly and deficits persisted in his other cognitive functions. Repeat brain magnetic resonance imaging at that time showed that he had responded to antibiotic treatment. Because Whipple disease can cause young-onset "dementia plus" syndromes that may leave patients with neurocognitive deficits even after apparently successful treatment, we recommend comprehensive neuropsychological assessment for early detection of residual and reversible cognitive processes and evaluation of treatment response.

Topics: Anti-Bacterial Agents; Brain; Ceftriaxone; Cognition; Cognition Disorders; Diagnosis, Differential; Humans; Infusions, Intravenous; Magnetic Resonance Imaging; Male; Memory Disorders; Middle Aged; Neurodegenerative Diseases; Neuropsychological Tests; Treatment Outcome; Whipple Disease

Neurological symptoms of patients suffering from neurodegenerative diseases such as Alzheimer's dementia (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS) often worsen during infections. We assessed the disease-modulating effects of recurrent systemic infections with the most frequent respiratory pathogen, Streptococcus pneumoniae, on the course of AD, PD, and ALS in mouse models of these neurodegenerative diseases [transgenic Tg2576 mice, (Thy1)-[A30P]alpha SYN mice, and Tg(SOD1-G93A) mice]. Mice were repeatedly challenged intraperitoneally with live S. pneumoniae type 3 and treated with ceftriaxone for 3 days. Infection caused an increase of interleukin-6 concentrations in brain homogenates. The clinical status of (Thy1)-[A30P]alpha SYN mice and Tg(SOD1-G93A) mice was monitored by repeated assessment with a clinical score. Motor performance was controlled by the tightrope test and the rotarod test. In Tg2576 mice, spatial memory and learning deficits were assessed in the Morris water maze. In none of the three mouse models onset or course of the disease as evaluated by the clinical tests was affected by the recurrent systemic infections performed. Levels of alpha-synuclein in brains of (Thy1)-[A30P]alpha SYN mice did not differ between infected animals and control animals. Plaque sizes and concentrations of A beta 1-40 and A beta 1-42 were not significantly different in brains of infected and uninfected Tg2576 mice. In conclusion, onset and course of disease in mouse models of three common neurodegenerative disorders were not influenced by repeated systemic infections with S. pneumoniae, indicating that the effect of moderately severe acute infections on the course of neurodegenerative diseases may be less pronounced than suspected.

Topics: Acute Disease; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Amyotrophic Lateral Sclerosis; Animals; Anti-Bacterial Agents; Ceftriaxone; Disease Models, Animal; Disease Progression; Interleukin-6; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Neurodegenerative Diseases; Neuropsychological Tests; Parkinson Disease; Plaque, Amyloid; Pneumonia, Bacterial; Recurrence; Streptococcal Infections; Streptococcus pneumoniae; Up-Regulation

Topics: Amyotrophic Lateral Sclerosis; Animals; Anti-Bacterial Agents; beta-Lactams; Brain; Ceftriaxone; Clinical Trials as Topic; Drug Evaluation, Preclinical; Excitatory Amino Acid Transporter 2; Glutamic Acid; Humans; Mice; Motor Neurons; Neurodegenerative Diseases; Spinal Cord; Synapses; Synaptic Transmission