ABSTRACT
Androgen deprivation therapy (ADT) for prostate cancer is associated with an increased risk of dementia, including Alzheimer's disease (AD). The mechanistic connection between ADT and AD-related cognitive impairment in patients with prostate cancer remains elusive. We established a clinically relevant prostate cancer-bearing AD mouse model to explore this. Both tumor-bearing and ADT induce complex changes in immune and inflammatory responses in peripheral blood and in the brain. ADT disrupts the integrity of the blood-brain barrier (BBB) and promotes immune cell infiltration into the brain, enhancing neuroinflammation and gliosis without affecting the amyloid plaque load. Moreover, treatment with natalizumab, an FDA-approved drug targeting peripheral immune cell infiltration, reduces neuroinflammation and improves cognitive function in this model. Our study uncovers an inflammatory mechanism, extending beyond amyloid pathology, that underlies ADT-exacerbated cognitive deficits, and suggests natalizumab as a potentially effective treatment in alleviating the detrimental effects of ADT on cognition.
Subject(s)
Alzheimer Disease , Androgen Antagonists , Blood-Brain Barrier , Brain , Cognitive Dysfunction , Disease Models, Animal , Animals , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Alzheimer Disease/metabolism , Male , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/pathology , Cognitive Dysfunction/etiology , Mice , Brain/drug effects , Brain/pathology , Brain/metabolism , Humans , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Androgen Antagonists/adverse effects , Androgen Antagonists/pharmacology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Natalizumab/adverse effects , Natalizumab/pharmacology , Natalizumab/therapeutic use , Plaque, Amyloid/pathology , Plaque, Amyloid/drug therapyABSTRACT
Objective: To investigate the susceptibility to some conventional and non-conventional insecticides in laboratory and field larval populations of the West Nile vector Culex pipiens L. (Cx. pipiens), the dominant species in Jeddah Province, Saudi Arabia. Methods: The tested conventional insecticides were Actikil and Pesgard, while the non-conventional ones were Bacilod, Dudim and Baycidal. Probit analysis and photo-microscopical observations were carried out to shed light on acute toxicity in laboratory and field Cx. pipiens strains. Results: Cx. pipiens were more susceptible to Pesgard (LC50: 0.045 and 0.032 mg/L) than Actikil (0.052 and 0.038 mg/L) and Bacilod (0.129 and 0.104 mg/L), for the field and laboratory strains, respectively. Results showed that treatments with the chitin syn-thesis inhibitor Dudim and Baycidal evoked morphological effects similar to those induced by other insect growth regulators. According to IC50 values obtained (concen-tration which to inhibit the emergence of 50%of mosquito adults), the compound Dudim (0.000 3 and 0.000 1 mg/L) was more effective against Cx. pipiens L. mosquitoes than Baycidal (0.000 4 and 0.000 3 mg/L) for both the field and laboratory strains, respectively. Conclusions: Our results provide baseline data to enhance control programs and orient public health decisions on the selection of pesticides against mosquito vectors in Saudi Arabia.