Cognitive recovery in the aged rat after stroke and anti-Nogo-A immunotherapy

Abstract

We have previously shown that immunotherapy directed against the protein Nogo-A leads to recovery on a skilled forelimb reaching task in rats after sensorimotor cortex stroke, which correlated with axonal and dendritic plasticity. Here we investigated anti-Nogo-A immunotherapy as an intervention to improve performance on a spatial memory task in aged rats after stroke, and whether cognitive recovery was correlated with structural plasticity. Aged rats underwent a unilateral distal permanent middle cerebral artery occlusion and one week later were treated with an anti-Nogo-A or control antibody. Nine weeks post-stroke, treated rats and normal aged rats were tested on the Morris water maze task. Following testing rats were sacrificed and brains processed for the Golgi-Cox method. Hippocampal CA3 and CA1 pyramidal and dentate gyrus granule cells were examined for dendritic length and number of branch segments, and CA3 and CA1 pyramidal cells were examined for spine density and morphology. Anti-Nogo-A immunotherapy given one week following stroke in aged rats improved performance on the reference memory portion of the Morris water maze task. However, this improved performance was not correlated with structural changes in the hippocampal neurons examined. Our finding of improved performance on the Morris water maze in aged rats after stroke and treatment with anti-Nogo-A immunotherapy demonstrates the promising therapeutic potential for anti-Nogo-A immunotherapy to treat cognitive deficits after stroke. The identification of sites of axonal and dendritic plasticity in the aged brain after stroke and treatment with anti-Nogo-A immunotherapy is still under investigation.

Constraint-Induced Movement Therapy Overcomes the Intrinsic Axonal Growth–Inhibitory Signals in Stroke Rats

“…Several studies showed that reducing expression of myelin-associated glycoprotein and Nogo-A may be a possible treatment to enhance cognitive recovery after brain injury. 33,34 For example, anti-Nogo-A immunotherapy improved performance in the water maze task after stroke with aged rats. 33 Morphological axonal or dendritic changes in the hippocampus or other brain areas may underlie the improved spatial memory.…”

“…33,34 For example, anti-Nogo-A immunotherapy improved performance in the water maze task after stroke with aged rats. 33 Morphological axonal or dendritic changes in the hippocampus or other brain areas may underlie the improved spatial memory. 33 There are studies demonstrating that the efficacy of rehabilitative therapies after stroke is time dependent.…”

“…33 Morphological axonal or dendritic changes in the hippocampus or other brain areas may underlie the improved spatial memory. 33 There are studies demonstrating that the efficacy of rehabilitative therapies after stroke is time dependent. 35,36 Rehabilitation initiated 5 days or 14 days after cerebral ischemia not only significantly improved functional recovery, but also enhanced structural plasticity, such as increased dendritic growth within the contralateral cortex of rats.…”

Promoting Neurological Recovery in the Post-Acute Stroke Phase: Benefits and Challenges

“…In the case of BMSC delivery, neurological improvements persisted in middle-aged rats (12 months) for at least one year [26]. Although neurological recovery was successful, dendritic and synaptic plasticity of hippocampal CA3 and CA1 pyramidal and dentate gyrus granule cells were not influenced by NogoA antibodies in aged (24 months) rats; yet improvements in spatial memory were present [73]. Indeed, the expression of plasticity-related proteins in neurons differs between young and old animals.…”

Neuroprotective effects of NEP1-40 and fasudil on Nogo-A expression in neonatal rats with hypoxic-ischemic brain damage

“…Cerebral HIBD has been reported to impair memory because hippocampal neurons are susceptible to the deleterious effects of HI, and because the hippocampus is involved in the regulation of memory (Gillani et al, 2010). We found that NEP1-40 and fasudil resulted in a considerable reduction in HI-induced brain injury, when measured in the terms of the response capacity, food response and crawling.…”