Assessing the Contribution Antiretroviral Therapy to Neuronal Damage and Death as a Mediator of Cognitive Decline in HIV-Associated Neurocognitive Disorders

The advent of combination antiretroviral therapy (ART) in 1996 revolutionized the treatment of HIV/AIDS and significantly decreased the incidence of HIV-associated neurocognitive disorders (HAND), a spectrum of HIV-related CNS dysfunctions ranging from mild cognitive deficits to severe dementia. Although the long-term prognosis for ART-treated, HIV-positive individuals continues to improve, the life-expectancy for this population remains 10-30 years less than that of uninfected individuals. Additionally, the clinical and pathologic presentation of HAND has evolved from a subacute, subcortical encephalitic condition, to a prolonged, cortical, neurodegenerative disease with pathological features that resemble those found in Alzheimer Disease (AD). The specific mechanisms driving these pathological changes remain unknown, although emerging evidence suggests that antiretroviral neurotoxicity may be a significant contributing factor. Here, we examined mechanisms by which antiretroviral drugs induce stress in neurons leading to changes in amyloid precursor protein (APP) processing. Utilizing in vitro models of acute ART exposure, we observed that HIV protease inhibitor (PI)-class ART drugs robustly active the unfolded protein response in primary neurons leading to translational de-repression of beta-site cleaving enzyme 1 (BACE1) by phosphorylated eIF2alpha; and augmented amyloidogenic cleave of APP. These results were corroborated in ART-treated, SIV-infected macaques were we saw increased hippocampal expression of BACE1 AND IN HAND patients where we also found similar increases in BACE1 expression in CA1 and CA3 hippocampal regions accompanied by accumulation of intraneuronal oligomeric Abeta;. Finally, we demonstrate that inhibition of neuronal BACE1 activity in vitro protects cells from hydrogen peroxide and antiretroviral drug-mediated toxicity. From this body of work, we conclude that PI-class antiretroviral drugs play a prominent role in stress activation of CNS neurons leading to aberrant changes in APP processing and potentially contributing to neuronal damage and death in HAND. Lastly, we have identified BACE1 as an important adjunctive therapeutic target in the treatment of chronic cognitive decline in ART-medicated, HIV-positive individuals

Diagnosis and management of neuropathic pain : review of literature and recommendations of the Polish Association for the Study of Pain and the Polish Neurological Society : part one

Neuropathic pain still present a major diagnostic and therapeutic challenge despite considerable progress in understanding of its mechanisms and publication of number of studies which assessed the efficacy and safety of drugs used in the symptomatic treatment. In practice, it is diagnosed less frequently than recognised in the epidemiological studies, and many patients do not achieve satisfactory outcomes of treatment. A multidisciplinary team of Polish experts, commissioned by the Polish Association for the Study of Pain and the Polish Neurological Society, has reviewed the literature on neuropathic pain, with special focus on the published international recommendations, and formulated recommendations on neuropathic pain diagnosis and treatment, in accordance with the principles of evidence- based medicine. The paper presents also background information on the neuropathic pain definition, epidemiology, pathomechanism and method of assessment. The diagnosis of neuropathic pain may be established based on medical history and physical examination including special assessment of the somatosensory system. First-line drugs used in pharmacological management of neuropathic pain are: tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, gabapentin, pregabalin, opioids and lidocaine patches

Translational investigation and treatment of neuropathic pain

Neuropathic pain develops from a lesion or disease affecting the somatosensory system. Translational investigations of neuropathic pain by using different animal models reveal that peripheral sensitization, spinal and cortical plasticity may play critical roles in neuropathic pain. Furthermore, descending facilitatory or excitatory modulation may also act to enhance chronic pain. Current clinical therapy for neuropathic pain includes the use of pharmacological and nonpharmacological (psychological, physical, and surgical treatment) methods. However, there is substantial need to better medicine for treating neuropathic pain. Future translational researchers and clinicians will greatly facilitate the development of novel drugs for treating chronic pain including neuropathic pain