paliperidone-palmitate and Huntington-Disease

Through this brief report, we described our clinical considerations about the treatment of motor fluctuations and psychiatric comorbidities in Huntington's disease, for example, aggressiveness and obsessive-compulsive disorders. Indeed, as classical treatment, for example, olanzapine and risperidone, were inefficient to improve motor disorders in our patient, we postulated that motor fluctuations could be influenced by the pharmacokinetic profile of oral risperidone. So, in line with recent practice in schizophrenia, we proposed empirically paliperidone 1-month long-acting injections hypothesized to improve motor fluctuations, treatment so far reserved to Huntington's disease patients who are noncompliant to oral risperidone. Improvement was soon observed concerning motor fluctuations, but also aggressiveness, supporting our initial hypothesis.

Topics: Delayed-Action Preparations; Humans; Huntington Disease; Paliperidone Palmitate; Treatment Outcome

Oral antipsychotics are used to treat motor and behavioural disturbances in Huntington's disease (HD). However, patients with behavioural disturbances are often non-compliant, thus the oral route is inappropriate. The effects of antipsychotic long-acting injections (LAI) in HD are significantly underrepresented in literature. Paliperidone LAI (P-LAI), an atypical antipsychotic, has benefits over other antipsychotics LAI with its long dosing interval and no initial oral overlap, but has no documented cases for this indication. This case of a 45-year-old female highlights the use of P-LAI for severe aggression and chorea secondary to HD causing failed placement in assisted-care accommodation and mobility via an electronic-wheelchair. Three weeks after commencing treatment, she could walk unassisted, and displayed no aggression. After 10 months, she still had significant improvements and resided in the same accommodation for 6 months without any concern. Thus, this case suggests that P-LAI may be a treatment option for non-compliant HD patients.

Topics: Administration, Oral; Antipsychotic Agents; Delayed-Action Preparations; Female; Humans; Huntington Disease; Injections, Intramuscular; Mental Disorders; Middle Aged; Motor Disorders; Paliperidone Palmitate

Huntington's disease (HD) is a neurodegenerative disease marked by an expanded polyglutamine (polyQ) tract on the huntingtin (HTT) protein that may cause transcriptional dysfunction. This study aimed to investigate the regulation and function of P-glycoprotein, an important efflux transporter, in brain capillaries in HD. The results showed that, compared with the littermate controls, R6/2 HD transgenic mice with the human mutant HTT gene had higher levels of P-glycoprotein mRNA and protein and enhanced NF-κB activity in their brain capillaries. Higher P-glycoprotein expression was also observed in the brain capillaries of human HD patients. Consistent with this enhanced P-glycoprotein expression, brain extracellular levels and brain-to-plasma ratios of the antipsychotic agents risperidone and paliperidone were significantly lower in R6/2 mice than in their littermate controls. Exogenous expression of human mutant HTT protein with expanded polyQ (mHTT-109Q) in HEK293T cells enhanced the levels of P-glycoprotein transcripts and NF-κB activity compared with cells expressing normal HTT-25Q. Treatment with the IKK inhibitor, BMS-345541, decreased P-glycoprotein mRNA level in cells transfected with mHTT-109Q or normal HTT-25Q In conclusion, mutant HTT altered the expression of P-glycoprotein through the NF-κB pathway in brain capillaries in HD and markedly affected the availability of P-glycoprotein substrates in the brain.

Topics: Animals; Antipsychotic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Blood-Brain Barrier; Capillaries; Gene Expression Regulation; HEK293 Cells; Humans; Huntingtin Protein; Huntington Disease; Mice, Transgenic; NF-kappa B; Paliperidone Palmitate; Reverse Transcriptase Polymerase Chain Reaction; Risperidone

Quinolinic acid (QA)-induced neurotoxicity involves a cascade of events such as increased calcium concentration in cytoplasm, exhaustive ATP depletion, oxidative stress, as well as selective GABAergic, dopaminergic, and cholinergic neuronal death. Clinical data hint towards the connection between signalling of dopaminergic system and efficient amelioration of chorea following a tetrabenazine administration in Huntington's disease patients. Therefore, the present study has been designed to explore the neuroprotective potential of paliperidone, an active metabolite of risperidone (a dopaminergic antagonist) against QA-induced neurotoxicity and related complications in rats. QA (200 nmol) was administered bilaterally to the striatum over a period of 2 min by means of a 28-gauge stainless steel needle attached to a Hamilton syringe. The study protocol involves seven treatment groups (n = 12): naïve, sham, control (QA), paliperidone (0.5, 1 and 2 mg/kg) and paliperidone (2) per se. Single bilateral intrastriatal injection of QA (200 nmol/2 μl saline) significantly caused motor incordination, memory impairment, oxidative damage, decrease in biogenic amines levels, cellular alterations (TNF-α, IL-6, PGE2, PGF2α, caspase-3, BDNF, mitochondrial function) and damage of striatal neurons compared to the sham treatment. Treatment with paliperidone (0.5, 1 and 2 mg/kg) for 21 days significantly attenuated the QA-induced behavioural (motor and memory function), neurochemical (antioxidant enzymes and biogenic amines) and cellular alterations, as well as striatal neurodegeneration. The study indicated that modulation of dopaminergic pathway by paliperidone treatment could be a useful approach in the management of motor and memory abnormality in HD patients.

Topics: Acetylcholinesterase; Animals; Biogenic Amines; Body Weight; Corpus Striatum; Huntington Disease; Isoxazoles; Male; Maze Learning; Memory Disorders; Mitochondria; Movement Disorders; Neurons; Neuroprotective Agents; Oxidative Stress; Oxygen; Paliperidone Palmitate; Pyrimidines; Quinolinic Acid; Rats, Wistar