A Novel Anti-Inflammatory d-Peptide Inhibits Disease Phenotype Progression in an ALS Mouse Model

Abstract Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by selective neuronal death in brain stem and spinal cord. The cause is unknown, but an increasing evidence has firmly certified that neuroinflammation plays a key role in ALS pathogenesis. Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and has been implicated as driver of disease progression. Here, we describe two treatment studies demonstrating the therapeutic potential of a tandem version of the well-known all-d-peptide RD2 (RD2RD2) in a transgenic mouse model of Alzheimer’s disease (APP/PS1) and in a transgenic mouse model of ALS (SOD1*G93A).Methods:APP/PS1 and SOD1*G93A mice were treated intraperitoneally for four weeks mice with RD2RD2 vs placebo. APP/PS1 brain and plasma samples were histologically and biochemically analysed for inflammatory markers, gliosis and amyloid pathology. SOD1*G93A mice were tested longitudinally during treatment in various behavioural and motor coordination tests. Brain and spinal cord samples were investigated immunohistochemically for gliosis and neurodegeneration.Results: Treatment in APP/PS1 mice revealed significant reduction in glial cell activation in the brain and significantly lower levels of inflammatory cytokines in plasma. RD2RD2 treatment in SOD1*G93A mice resulted not only in a reduction of activated astrocytes and microglia in both brain stem and lumbar spinal cord but also in a rescue of neurons in the motor cortex. Moreover, behavioural tests revealed that the disease phenotype of SOD1*G93A mice is halted during treatment.Conclusion: Based on the presented results, we conclude that RD2RD2 is a potential therapeutic candidate against ALS.

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A Novel Anti-inflammatory D-peptide Halts Disease Phenotype Progression in an Als Mouse Model

10.21203/rs.3.rs-30893/v1 ◽

2020 ◽

Author(s):

Julia Post ◽

Vanessa Kogel ◽

Anja Schaffrath ◽

Philipp Lohmann ◽

Nadim Joni Shah ◽

...

Keyword(s):

Spinal Cord ◽

Mouse Model ◽

Brain Stem ◽

Transgenic Mouse ◽

Cell Activation ◽

Therapeutic Potential ◽

Transgenic Mouse Model ◽

Lumbar Spinal Cord ◽

Disease Phenotype ◽

Model Of Alzheimer’S Disease

Abstract Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by selective neuronal death in brain stem and spinal cord. The cause is unknown, but an increasing evidence has firmly certified that neuroinflammation plays a key role in ALS pathogenesis. Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and has been implicated as driver of disease progression. Here, we describe two treatment studies demonstrating the therapeutic potential of a tandem version of the well-known all-d-peptide RD2 (RD2RD2) in a transgenic mouse model of Alzheimer’s disease (APP/PS1) and in a transgenic mouse model of ALS (SOD1*G93A).Methods:APP/PS1 and SOD1*G93A mice were treated intraperitoneally for four weeks mice with RD2RD2 vs placebo. APP/PS1 brain and plasma samples were histologically and biochemically analysed for inflammatory markers, gliosis and amyloid pathology. SOD1*G93A mice were tested longitudinally during treatment in various behavioural and motor coordination tests. Brain and spinal cord samples were investigated immunohistochemically for gliosis and neurodegeneration.Results: Treatment in APP/PS1 mice revealed significant reduction in glial cell activation in the brain and significantly lower levels of inflammatory cytokines in plasma. RD2RD2 treatment in SOD1*G93A mice resulted not only in a reduction of activated astrocytes and microglia in both brain stem and lumbar spinal cord but also in a rescue of neurons in the motor cortex. Moreover, behavioural tests revealed that the disease phenotype of SOD1*G93A mice is halted during treatment.Conclusion: Based on the presented results, we conclude that RD2RD2 is a potential therapeutic candidate against ALS.

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Descending inhibitory influences from periaqueductal gray, nucleus raphe magnus, and adjacent reticular formation. I. Effects on lumbar spinal cord nociceptive and nonnociceptive neurons

Journal of Neurophysiology ◽

10.1152/jn.1983.49.4.932 ◽

1983 ◽

Vol 49 (4) ◽

pp. 932-947 ◽

Cited By ~ 115

Author(s):

B. G. Gray ◽

J. O. Dostrovsky

Keyword(s):

Spinal Cord ◽

Brain Stem ◽

Periaqueductal Gray ◽

Spinal Cord Dorsal Horn ◽

Lumbar Spinal Cord ◽

Nucleus Raphe Magnus ◽

Nucleus Reticularis ◽

Raphe Magnus ◽

Lumbar Spinal ◽

The Brain

1. This study examined the inhibitory effects of conditioning stimuli delivered to the periaqueductal gray (PAG), nucleus cuneiformis (CU), nucleus raphe magnus (NRM), nucleus reticularis gigantocellularis (NGC), and nucleus reticularis magnocellularis (NMC) on functionally identified neurons of the lumbar spinal cord dorsal horn in chloralose-anesthetized or decerebrate cats. 2. Neurons were classified according to their responses to a variety of cutaneous stimuli as low-threshold mechanoreceptive (LTM), wide dynamic range (WDR), or nociceptive specific (NS). The major aim of this study was to determine whether there was a difference in the effectiveness of the brain stem stimulation-produced inhibition of nociceptive (noci) neurons (consisting of both WDR and NS neurons) and the LTM non-nociceptive (nonnoci) neurons. There were no statistical differences in the susceptibility of WDR and NS neurons to brain stem-induced inhibition. 3. Most neurons tested could be inhibited by stimulation of any of the brain stem regions tested. In all cases the percentage of noci neurons inhibited from a given region was higher than the percentage of nonnoci neurons; however, this difference was only statistically significant in the case of NMC stimulation. 4. Threshold current intensities necessary to produce inhibition were determined for each neuron from each stimulation site. Although there was a trend for noci neurons to require slightly lower current intensities, there was in fact no statistically significant difference in the inhibitory thresholds between noci and nonnoci neurons for any of the regions tested. 5. A comparison of the mean threshold currents for the five regions studied revealed that the lowest stimulation currents were obtained in NMC with NRM, CU, NGC, and PAG, each requiring progressively higher current intensities in order to produce inhibition. 6. These results indicate that stimulation in PAG and NRM not only inhibits the responses of noci neurons but also those of nonnoci neurons. Moreover, stimulation in reticular regions adjacent to these two regions is effective in inhibiting the responses of both noci and nonnoci neurons.

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Does Motor Learning Occur in the Spinal Cord?

The Neuroscientist ◽

10.1177/107385849700300510 ◽

1997 ◽

Vol 3 (5) ◽

pp. 287-294 ◽

Cited By ~ 47

Author(s):

V. Reggie Edgerton ◽

Roland R. Roy ◽

Ray De Leon Niranjala Tillakaratne ◽

John A. Hodgson

Keyword(s):

Spinal Cord ◽

Motor Task ◽

Lumbar Spinal Cord ◽

Lumbosacral Spinal Cord ◽

Patterns Of Use ◽

The Neural Network ◽

The Central Nervous System ◽

Network Plasticity ◽

Lumbar Spinal ◽

The Brain

It is becoming clear that the plasticity of the sensory-motor networks of the adult mammalian lumbosacral spinal cord is much greater than and is more dependent on the specific patterns of use than has been previously assumed. Using a wide variety of experimental paradigms in which the lumbar spinal cord is isolated from the brain, it has been shown that the lumbosacral spinal cord can learn to execute stepping or standing more successfully if that specific task is practiced. It also appears that the sensory input associated with the motor task and/or the manner in which it is interpreted by the spinal cord are important components of the neural network plasticity. Early evidence suggests that several neurotransmitter systems in the spinal cord, to include glycinergic and GABAergic systems, adapt to repetitive use. These studies extend a growing body of evidence suggesting that memory and learning are widely distributed phenomena within the central nervous system. NEUROSCIENTIST 3:287–294, 1997

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Differential expression and alternative splicing of genes in lumbar spinal cord of an amyotrophic lateral sclerosis mouse model

Brain Research ◽

10.1016/j.brainres.2010.03.075 ◽

2010 ◽

Vol 1340 ◽

pp. 52-69 ◽

Cited By ~ 11

Author(s):

Huifang Chen ◽

Yansu Guo ◽

Ming Hu ◽

Weisong Duan ◽

Geng Chang ◽

...

Keyword(s):

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Alternative Splicing ◽

Mouse Model ◽

Differential Expression ◽

Lumbar Spinal Cord ◽

Lumbar Spinal ◽

Lateral Sclerosis

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Sexual Experience Induces the Expression of Gastrin-Releasing Peptide and Oxytocin Receptors in the Spinal Ejaculation Generator in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms221910362 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10362

Author(s):

Takumi Oti ◽

Ryota Ueda ◽

Ryoko Kumagai ◽

Junta Nagafuchi ◽

Takashi Ito ◽

...

Keyword(s):

Spinal Cord ◽

Sexual Activity ◽

Neural Circuits ◽

Sexual Experience ◽

Lumbar Spinal Cord ◽

Gastrin Releasing Peptide ◽

Oxytocin Receptors ◽

Male Sexual Function ◽

Lumbar Spinal ◽

The Brain

Male sexual function in mammals is controlled by the brain neural circuits and the spinal cord centers located in the lamina X of the lumbar spinal cord (L3–L4). Recently, we reported that hypothalamic oxytocin neurons project to the lumbar spinal cord to activate the neurons located in the dorsal lamina X of the lumbar spinal cord (dXL) via oxytocin receptors, thereby facilitating male sexual activity. Sexual experiences can influence male sexual activity in rats. However, how this experience affects the brain–spinal cord neural circuits underlying male sexual activity remains unknown. Focusing on dXL neurons that are innervated by hypothalamic oxytocinergic neurons controlling male sexual function, we examined whether sexual experience affects such neural circuits. We found that >50% of dXL neurons were activated in the first ejaculation group and ~30% in the control and intromission groups in sexually naïve males. In contrast, in sexually experienced males, ~50% of dXL neurons were activated in both the intromission and ejaculation groups, compared to ~30% in the control group. Furthermore, sexual experience induced expressions of gastrin-releasing peptide and oxytocin receptors in the lumbar spinal cord. This is the first demonstration of the effects of sexual experience on molecular expressions in the neural circuits controlling male sexual activity in the spinal cord.

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The Expanding Therapeutic Potential of Neuronal KCC2

Cells ◽

10.3390/cells9010240 ◽

2020 ◽

Vol 9 (1) ◽

pp. 240 ◽

Cited By ~ 2

Author(s):

Bor Luen Tang

Keyword(s):

Spinal Cord ◽

Mouse Model ◽

Neurological Disorders ◽

Healthy Adult ◽

Therapeutic Potential ◽

Reversal Potential ◽

Memory Deficits ◽

Inhibitory Input ◽

Disease Phenotype ◽

Neural Transmission

Dysfunctions in GABAergic inhibitory neural transmission occur in neuronal injuries and neurological disorders. The potassium–chloride cotransporter 2 (KCC2, SLC12A5) is a key modulator of inhibitory GABAergic inputs in healthy adult neurons, as its chloride (Cl−) extruding activity underlies the hyperpolarizing reversal potential for GABAA receptor Cl− currents (EGABA). Manipulation of KCC2 levels or activity improve symptoms associated with epilepsy and neuropathy. Recent works have now indicated that pharmacological enhancement of KCC2 function could reactivate dormant relay circuits in an injured mouse’s spinal cord, leading to functional recovery and the attenuation of neuronal abnormality and disease phenotype associated with a mouse model of Rett syndrome (RTT). KCC2 interacts with Huntingtin and is downregulated in Huntington’s disease (HD), which contributed to GABAergic excitation and memory deficits in the R6/2 mouse HD model. Here, these recent advances are highlighted, which attest to KCC2’s growing potential as a therapeutic target for neuropathological conditions resulting from dysfunctional inhibitory input.

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Assessing the Effects of Parthenolide on Inflammation, Bone Loss, and Glial Cells within a Collagen Antibody-Induced Arthritis Mouse Model

Mediators of Inflammation ◽

10.1155/2020/6245798 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

B. Williams ◽

F. Lees ◽

H. Tsangari ◽

M. R. Hutchinson ◽

E. Perilli ◽

...

Keyword(s):

Spinal Cord ◽

Mouse Model ◽

Calcium Binding ◽

Bone Destruction ◽

Suppressive Effect ◽

Lumbar Spinal Cord ◽

Cell Reactivity ◽

Chronic Inflammatory Response ◽

Radiocarpal Joint ◽

Lumbar Spinal

Rheumatoid arthritis is characterised by a chronic inflammatory response resulting in destruction of the joint and significant pain. Although a range of treatments are available to control disease activity in RA, bone destruction and joint pain exist despite suppression of inflammation. This study is aimed at assessing the effects of parthenolide (PAR) on paw inflammation, bone destruction, and pain-like behaviour in a mild collagen antibody-induced arthritis (CAIA) mouse model. CAIA was induced in BALB/c mice and treated daily with 1 mg/kg or 4 mg/kg PAR. Clinical paw inflammation was scored daily, and mechanical hypersensitivity was assessed on alternate days. At end point, bone volume and swelling in the paws were assessed using micro-CT. Paw tissue sections were assessed for inflammation and pre-/osteoclast-like cells. The lumbar spinal cord and the periaqueductal grey (PAG) and rostral ventromedulla (RVM) regions of the brain were stained for glial fibrillary acidic protein (GFAP) and ionised calcium-binding adaptor molecule 1 (IBA1) to assess for glial reactivity. Paw scores increased in CAIA mice from days 5-10 and were reduced with 1 mg/kg and 4 mg/kg PAR on days 8-10. Osteoclast-like cells on the bone surface of the radiocarpal joint and within the soft tissue of the hind paw were significantly lower following PAR treatment (p<0.005). GFAP- and IBA1-positive cells in the PAG and RVM were significantly lower following treatment with 1 mg/kg (p<0.0001 and p=0.0004, respectively) and 4 mg/kg PAR (p<0.0001 and p=0.001, respectively). In the lumbar spinal cord, IBA1-positive cells were significantly lower in CAIA mice treated with 4 mg/kg PAR (p=0.001). The findings indicate a suppressive effect of both low- and moderate-dose PAR on paw inflammation, osteoclast presence, and glial cell reactivity in a mild CAIA mouse model.

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Brain stem involvement in the effects of chlorpromazine on the monosynaptic reflex of the rat lumbar spinal cord

General Pharmacology The Vascular System ◽

10.1016/0306-3623(86)90178-3 ◽

1986 ◽

Vol 17 (4) ◽

pp. 379-383 ◽

Cited By ~ 5

Author(s):

Masataka Hino ◽

Hideki Ono ◽

Hideomi Fukuda

Keyword(s):

Spinal Cord ◽

Brain Stem ◽

Monosynaptic Reflex ◽

Lumbar Spinal Cord ◽

Lumbar Spinal

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P2X7 antagonism using Brilliant Blue G reduces body weight loss and prolongs survival in female SOD1G93Aamyotrophic lateral sclerosis mice

PeerJ ◽

10.7717/peerj.3064 ◽

2017 ◽

Vol 5 ◽

pp. e3064 ◽

Cited By ~ 18

Author(s):

Rachael Bartlett ◽

Vanessa Sluyter ◽

Debbie Watson ◽

Ronald Sluyter ◽

Justin J. Yerbury

Keyword(s):

Spinal Cord ◽

Weight Loss ◽

Body Weight ◽

Motor Coordination ◽

Body Weight Loss ◽

Clinical Score ◽

Lumbar Spinal Cord ◽

Reduced Body ◽

End Stage ◽

Lumbar Spinal

BackgroundAmyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterised by the accumulation of aggregated proteins, microglia activation and motor neuron loss. The mechanisms underlying neurodegeneration and disease progression in ALS are unknown, but the ATP-gated P2X7 receptor channel is implicated in this disease. Therefore, the current study aimed to examine P2X7 in the context of neurodegeneration, and investigate whether the P2X7 antagonist, Brilliant Blue G (BBG), could alter disease progression in a murine model of ALS.MethodsHuman SOD1G93Atransgenic mice, which normally develop ALS, were injected with BBG or saline, three times per week, from pre-onset of clinical disease (62–64 days of age) until end-stage. During the course of treatment mice were assessed for weight, clinical score and survival, and motor coordination, which was assessed by rotarod performance. Various parameters from end-stage mice were assessed as follows. Motor neuron loss and microgliosis were assessed by immunohistochemistry. Relative amounts of lumbar spinal cord SOD1 and P2X7 were quantified by immunoblotting. Serum monocyte chemoattractant protein-1 was measured by ELISA. Splenic leukocyte populations were assessed by flow cytometry. Relative expression of splenic and hepatic P2X7 mRNA was measured by quantitative real-time PCR. Lumbar spinal cord SOD1 and P2X7 were also quantified by immunoblotting in untreated female SOD1G93Amice during the course of disease.ResultsBBG treatment reduced body weight loss in SOD1G93Amice of combined sex, but had no effect on clinical score, survival or motor coordination. BBG treatment reduced body weight loss in female, but not male, SOD1G93Amice. BBG treatment also prolonged survival in female, but not male, SOD1G93Amice, extending the mean survival time by 4.3% in female mice compared to female mice treated with saline. BBG treatment had no effect on clinical score or motor coordination in either sex. BBG treatment had no major effect on any end-stage parameters. Total amounts of lumbar spinal cord SOD1 and P2X7 in untreated female SOD1G93Amice did not change over time.DiscussionCollectively, this data suggests P2X7 may have a partial role in ALS progression in mice, but additional research is required to fully elucidate the contribution of this receptor in this disease.

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