<span style="mso-bidi-font-size: 18.0pt;">Yokukan-San and Tetracycline Treatment for Alzheimer’s Disease

Alzheimer&rsquo;s disease (AD) is a progressive neurological disorder that causes memory loss, cognitive decline, and behavioral changes. AD pathologies involve different factors, including damage of cholinergic neurons, extracellular deposition of &beta;-amyloid (A&beta;) into senile plaques, intracellular accumulation of hyperphosphorylated tau protein, microglia-related neuroinflammation, and oxidative stress. Several medications, such as cholinesterase inhibitors, N-Methyl-D-aspartate receptor antagonists, and immunotherapy drugs, are administered for AD treatment. Along with AD-related neurological disorders, behavioral and psychological symptoms of dementia (BPSD) are also prevalent in individuals with AD. Pharmacological treatments for BPSD include antipsychotics, memantine, and others. Yokukan-san (YKS) is a traditional Japanese Kampo medicine. YKS contains a blend of several herbs, including Uncaria uncis cum ramulus, Angelicae radix, Bupleurum radix, and others. It has been efficacious against BPSD; thus, it was officially approved for BPSD treatment in Japan. Recently, the anti-AD effects of YKS have attracted considerable attention. Uncaria uncis cum ramulus managed AD by reducing A&beta; accumulation, decreasing abnormally hyperphosphorylated tau protein, and inhibiting acetylcholinesterase. Similarly, Angelicae radix has improved memory deficits in a rat AD model by reducing A&beta; levels, promoting cholinergic function, and decreasing oxidative stress and neuroinflammation. Tetracyclines (i.e., minocycline and doxycycline) popularly exhibit anti-inflammatory effects by inhibiting microglia. Moreover, minocycline has reduced A&beta; production and hyperphosphorylation of tau protein. Experimental AD models demonstrated that minocycline and doxycycline improved cognitive/learning, and memory deficits, respectively. Therefore, minocycline and doxycycline are efficacious against AD. Multidrug treatment is more effective than single-drug treatment because of the synergistic effects associated with the different mechanisms of action of involved drugs. In the absence of currently effective and low-priced treatments, YKS and tetracycline are proposed for AD treatment.