Differentiated Cerebrovascular Effects of Physostigmine and Tacrine in Cortical Areas Deafferented from the Nucleus Basalis Magnocellularis Suggest Involvement of Basalocortical Projections to Microvessels

Abstract

Cholinesterase inhibitors used to treat Alzheimer's disease according to the principle of cholinergic replacement therapy have proved to be less beneficial than expected. The present study was designed to investigate the cerebrovascular response to physostigmine and tacrine in the experimental model of lesioning of the nucleus basalis magnocellularis (NBM), a model involving a cholinergic deficit. Regional cerebral blood flow was measured by the [14C]iodoantipyrine tissue sampling technique in conscious rats infused with i.v. physostigmine (0.2 mg/kg/h), tacrine (8 mg/kg/h), or saline, 3-5 weeks after unilateral lesion of the NBM with ibotenic acid. Physostigmine and tacrine dose-dependently increased blood flow in most cortical and subcortical regions compared to the control group. However, physostigmine caused smaller blood flow increases in several areas, mostly cortical, of the lesioned compared to the intact hemisphere. The converse was observed with tacrine. A facilitated circulatory response appeared in cortical areas deafferented from the NBM, especially in the frontal cortex. These results provide evidence for distinct NBM-dependent components of the cortical cerebrovascular effects of physostigmine and tacrine. They suggest the involvement of different cellular postsynaptic targets of the NBM. The physostigmine-type effects could involve direct projects onto an inhibitory cortical interneuron supersensitized by deafferentation. This arrangement may explain why physostigmine and perhaps other cholinergic agonists are unable to specifically compensate for a deficit in NBM functioning. The tacrine-type effects presumably involve projections to the microvasculature, including perivascular astrocytes. The neurovascular junction would be sensitized by deafferentation from the NBM. Our data suggest that the regulatory mechanisms of blood flow originating in the NBM might constitute a target of neurodegenerative processes of Alzheimer's disease.

Cerebral microvascular pathology in aging and Alzheimer's disease

“…According to the expectations, a significant drop in cortical CBF was detected in the ipsilateral hemisphere 1-5 weeks after the lesion (Fig. 9) (Gomi et al, 1991;Peruzzi et al, 1996Peruzzi et al, , 2000 giving support to the assumption that the basal forebrain can modulate regional CBF in the neocortex. Hence, the loss of cortical cholinergic innervation in AD may contribute to the reported reduced CBF in the disease in a similar fashion.…”

“…When a group of human subjects was treated with scopolamine, a non-selective muscarinic ACh receptor blocker, a 20% decrease of CBF in the frontal cortex was detected (Honer et al, 1988). On the other hand, the application of the ACh-esterase inhibitors physostigmine and eptastigmine, which increase the extracellular level of endogenous ACh, led to a significant increase of CBF in a wide variety of brain regions in the rat and man (Scremin et al, 1993;Blin et al, 1997;Peruzzi et al, 2000). Although these experiments provided convincing evidence for the involvement of ACh in CBF regulation, the origin and exact target structures of the neurotransmitter still remained to be clarified.…”

“…The drop in CBF in the lesioned hemisphere is given as side-to-side difference compared to the intact, contralateral side. Abbreviations: FRC, frontal cortex, PC, parietal cortex (modified from Peruzzi et al, 2000; reprinted by permission of The New York Academy of Sciences).…”

Review: Cerebral microvascular pathology in ageing and neurodegeneration

“…Possibly, this disconnection contributes to white matter lesion-induced cognitive dysfunction. Indeed, cholinesterase inhibitors can restore CBF after ablation of the nucleus basalis of Meynert [164]. There is reason for optimism that the brain can be rescued from extended periods of hypoperfusion.…”

Are Cerebrovascular White Matter Lesions an Early Sign of Vascular Cognitive Impairment and Vascular Dementia?

“…Choline esterase inhibition has a potency to restore CBF in the cerebral cortex after lesioning of the nucleus basalis of Meynert [77], and cerebral ischemia [78], and also upregulate cholinergic neurotransmission in the cerebral cortex. Concurrent evidence supports the efficacy of cholinesterase inhibitors in vascular dementia, which include donepezil [79,80] and ribastigmine [81,82].…”